supporting information · finds the largest cavity in the receptor protein; (2) ligand: a ligand in...
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Supporting Information
Design, synthesis and docking-based 3D-QSAR study of novel
2-substituted 2-aminopropane-1, 3-diols as potent and selective
agonists of sphingosine-1-phosphate 1 (S1P1) receptor
Yulin Tiana, Jing Jin
a, Xiaojian Wang
b, Weijuan Han
b, Gang Li
b, Wanqi Zhou
a, Qiong
Xiaoa, Jianguo Qi
a, Xiaoguang Chen
a, Dali Yin
a,*
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China
b Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability
Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical
Sciences, Beijing 100050, PR China
Contents Page No.
IP1 functional assay 2
Determination of in vivo lymphopenia activitiy 2
Determination of heart rate 2
Molecular docking 2-3
3D-QSAR study 3-5
Chemistry—General experimental information 5-6
Chemistry—Synthetic procedures and spectroscopic data of compounds 6-56
References 56-57
* Corresponding author. Tel.: + 86 10 63165248; fax: + 86 10 63165248.
E-mail address: [email protected]
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IP1 functional assay
The CHO-S1P1 and CHO-S1P3 cells (purchased from Multispan) were plated into
384-well plates at 7×104 cells/well in Stimulation Buffer (containing LiCl). Then
different concentrations of test agonists were added into each well and incubated at 37℃
in 5% CO2 for 2 hours. Then D2-labeled IP1 and Ab-Cryp were subsequently added
into each well in lysis buffer and incubated for 1 h at room temperature according to
the manufacturer’s instructions. The plates were read in EnVision reader (PE
company), with data expressed as the ratio of 665 nm/615 nm fluorescence.1
Determination of in vivo lymphopenia activitiy
For the assessment of lymphopenia activities of agonists in conscious rats, male
Sprague-Dawley rats (200-220g) were purchased from Beijing Vital River Laboratory
Animal Technology Co, Ltd. The rats (three per group) were dosed through
intragastric administration with 1 mg/kg of test compound dissolved in DMSO. 10 μL
of blood was withdrawn via tail vein and the peripheral blood lymphocyte counts at
the time 0h, 1h, 4h, 8h, 12h and 24h after administration were assessed using
MEK-7222K hematology analyzer. The maximum lymphocyte-decreasing rate of test
compound (the maximum decreasing lymphocyte counts/ lymphocyte counts at 0h)
within 24h was calculated.2
Determination of heart rate
Male Sprague-Dawley rats (200-220g) were purchased from Beijing Vital River
Laboratory Animal Technology Co, Ltd. The conscious rats (three per group) were
dosed through intragastric administration with 10 mg/kg of test compound dissolved
in DMSO and vehicle. The heart rate at the time 0h, 1h, 4h, 8h, 12h and 24h after
administration were assessed using intelligent non-invasive blood pressure
measurement meter (Softron, Japan).
(All the in vivo experiments were performed in compliance with the relevant laws and institutional
guidelines. The institutional committee has approved the experiments.)
Molecular docking
29 S1P1 agonists were used for the docking research. For all 29 compounds, partial
atomic charges were calculated by the Gasteiger–Huckel method and energy
minimizations were carried out using the Tripos force field with a distance-dependent
dielectric and the Powell conjugate gradient algorithm with an energy convergence
gradient value of 0.05kcal/(mol*Å). The N-protonated and carboxylate forms of the
molecules, which are the prevalent species at physiological pH, were used in the
calculations.3 The crystal structure of S1P1 receptor complexing with inhibitor ML056
was obtained from the RCSB protein data bank (PDB entry code: 3V2Y).3-4
The
hetero atoms (cofactors, water molecules, and ligands) were removed and polar
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hydrogen atoms were added. The protein was optimized using molecular mechanics
method with the following parameters: a distance-dependent dielectric constant of 1.0;
nonbonded cutoff 8 Å, AMBER7 FF99 force field and AMBER7 FF99 charges; and
conjugate gradient minimization until the energy gradient RMS < 0.05kcal/(mol*Å).
Other parameters are established by default in software. All the calculations were
performed using SYBYL-X-2.0.
Surflex-Dock in SYBYL-X-2.0 was applied to study molecular docking, which
uses an empirical scoring function and a patented search engine to dock ligands into a
protein’s binding site.5 Protomol, a computational representation of the intended
binding site to which putative ligands are aligned, is used to guide molecular docking5.
The production of protomol supplies three manners: (1) Automatic: Surflex-Dock
finds the largest cavity in the receptor protein; (2) Ligand: A ligand in the same
coordinate space as the receptor; (3) Residues: Specified residues in the receptor.6
Figure S1 Binding mode of compound ML056 within the binding site of S1P1 receptor. The
crystallized ligand is represented in green.
3D-QSAR study
To explore the specific contributions of steric, electrostatic, hydrophobic, hydrogen
bond acceptor and donor in binding modes for the 29 agonists with active site of S1P1
receptor, both COMFA and COMSIA studies were performed based on the binding
conformational alignment from the molecular docking. The COMFA/COMSIA results
were graphically interpreted by field contribution maps (contour maps) using the
STDEV*COEFF field type. The STDEV*COEFF is a standard deviation coefficient
with default values of 80% favored contribution and 20% disfavored contribution.
COMFA The COMFA steric and electrostatic interactions were calculated using
the Tripos force field with a distance-dependent dielectric constant at all intersections
in a regularly spaced (2Å) grid taking a sp3 carbon atom as steric probe and a +1
charge as electrostatic probe. The cutoff value of 30 kcal/mol was adopted for both
steric and electrostatic field. The regression analysis was carried out using the full
cross-validated partial least squares (PLS) method (leave one out) with COMFA
standard options for scaling of variables.7 The column filter was set to 2.0 kcal/mol to
improve the signal-to-noise ratio by omitting the lattice points whose energy variation
was below the threshold. The final model (no-validation conventional analysis) was
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developed with the optimum number of components obtained in the cross-validated
step.
COMSIA COMSIA fields were derived with the same lattice as the COMFA used.
Five descriptor, i.e. steric (S), electrostatic (E), hydrophobic (H), hydrogen bond
donor (D) and hydrogen bond acceptor (A) were evaluated at grid lattice point using a
common probe atom of 1 Å radius, as well as the charge, hydrophobicity, and
hydrogen bond properties of +1. COMSIA similarity indices (AF, K) for a molecule j
with atoms i at a grid point q were computed as Eq. 1,
n
i
r
ikkporbekFiqeWWjA
1
,
q
,
2
)(
(1)
where Wik is the actual value of the physicochemical property k of atom i, and Wprobe, k
is the value of the probe atom. A Gaussian type distance dependence was used
between the grid point q and each atom i of the molecule, where r represents the
distance. The attenuation factor (α) was set to 0.3 as default. The statistical evaluation
for the COMSIA analyses was performed in the same way for COMFA.
Model validation The COMFA and COMSIA descriptors were used as
independent variables and pEC50 as the dependent variable. PLS method was used to
linearly correlate these COMFA and COMSIA descriptors to the biological activity
values. PLS algorithm is a variation of principal component regression in which the
original variables are replaced by a small set of linear combination thereof.
The cross-validated correlation coefficient (q2) that resulted in optimum number of
components (N) and lowest standard error of estimation (SEE) was used as the
diagnostic tool to evaluate the predictive power of the QSAR model. Generally, the
model was considered predictable when q2 is larger than 0.5 and linear regression
analysis was considered significant when Non-cross validated value (r2) is greater
than 0.7. The r2, q
2 and SEE were calculated using the following equations (Eqs. 2, 3,
and 4):
r2=1-
n
i fiti
i i
YY
YY
1
2
n
1
2
)(
)( (2)
q2=1-
n
i cvi
n
i i
YY
YY
1
2
2
1
)(
)( (3)
SEE=N
YYi cvi
n
1
2)( (4)
where Yi=experimental value; Yfit=recalculated value; Y =mean value; Ycv=predicted
value; N= number of objects.
The external predictive power of the generated model was evaluated by predicting
the activities of the test set compounds. The predictive correlation coefficient r2
pred,
based on test set molecules is computed by using Eq.5,
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r2
pred=SD
PRESSSD )( (5)
where SD is the sum of squared deviation between the biological activities of the test
set molecule and the mean activity of the training set molecules, and PRESS presents
the sum of squared deviations between the experimental and predicted activities of the
test molecules.
Table S1 Experimental and predicted S1P1 agonistic activities of target compounds for
COMFA and COMSIA models
Compound pEC50 COMFA COMSIA
Predicted Residuals Predicted Residuals
3 1.854 1.681 0.173 1.473 0.381
5a 0.932 0.698 0.234 0.866 0.066
14a a 1.039 0.848 0.191 0.613 0.426
14b 1.432 1.605 -0.173 1.699 -0.267
14c 1.143 1.166 -0.023 0.954 0.189
14d 0.693 0.648 0.045 0.638 0.055
14e a 0.467 0.416 0.051 0.425 0.042
14f 0.053 0.035 0.018 0.282 -0.229
14g 0.031 -0.023 0.054 -0.045 0.076
14h 0.097 0.037 0.06 0.156 -0.059
14i a 1.178 1.07 0.108 1.316 -0.138
21a a 1.067 0.986 0.081 0.931 0.136
21b 0.764 0.838 -0.074 0.688 0.076
21c 0.804 0.801 0.003 0.746 0.058
21d a 1.456 1.42 0.036 1.427 0.029
21e a 0.595 0.613 -0.018 0.631 -0.036
25a 1.292 1.331 -0.039 1.393 -0.101
25b a 0.277 0.405 -0.128 0.19 0.087
25c 0.483 0.427 0.056 0.373 0.11
30a 1.388 1.417 -0.029 1.384 0.004
30b 1.051 1.088 -0.037 1.256 -0.205
30c 1.703 1.693 0.01 1.577 0.126
33 1.318 1.284 0.034 1.447 -0.129
40a 1.178 1.222 -0.044 1.145 0.033
40b 1.277 1.255 0.022 1.327 -0.05
40c 1.854 1.801 0.053 1.857 -0.003
47 1.569 1.538 0.031 1.534 0.035
54a 0.057 0.175 -0.118 0.09 -0.033
54b 0.199 0.22 -0.021 0.264 -0.065
a test set
Chemistry
General experimental information
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Equipment Melting points were determined on Yanaco MP-J3 microscope melting
point apparatus; NMR spectra were recorded on a Varian-600、Bruker-500、
Mercury-400 和 Mercury-300 spectrometer; Chemical shifts are referenced to the
residual solvent peak and reported in ppm (δ scale) and all coupling constant (J)
values are given in Hz. The following multiplicity abbreviations are used: (s) singlet,
(d) doublet, (t) triplet, (q) quartet, (m) multiplet, and (br) broad; ESI-MS and
HR-ESI-MS data were measured on Micromass AutoSpec Ultima-TOF spectrometer;
Flash column chromatography was performed on Biotage Isolera one.
Solvents and chemicals CH2Cl2 was distilled under Ar2 from P2O5 and stored over
4Å molecular sieves. THF was distilled under Ar2 from sodium/benzophenone and
stored over 4Å molecular sieves. All other solvents and chemicals were obtained from
commercial sources and used without further purification.
Synthetic procedures and spectroscopic data of compounds
Synthesis of 2-chloro-1-(4-4-ethylphenethyl)phenyl)ethanone (7a)
Chloroacetyl chloride (3.9 g, 34.9 mmol) in CH2Cl2(10mL) was added dropwise to
a cooled solution (0°C) of 6a (7.0 g, 33.3 mmol) in CH2Cl2(80mL), then AlCl3 (4.9 g,
36.6 mmol) was added in portions in 30min. The solution was then allowed to return
to room temperature and stirred for further 2 h. The mixture was poured slowly into
2NHCl-ice mixture (50mL) and stirred for 1 h. The aqueous phase was extracted with
CH2Cl2 (10mL×3). The combined organic layers were washed with saturated aq.
NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was
purified by silica gel flash column chromatography (EtOAc/PE) to afford compound
7a (4.4g, 33% yield) as yellow solid.
mp: 16-18 oC;
1H NMR (300 MHz, CDCl3): δ 7.87 (d, J = 8.1 Hz, 2 H) 7.28 (d, J =
7.8 Hz, 2 H) 7.09 (dd, J = 14.1 Hz, 7.8 Hz, 4 H) 4.68 (s, 2 H) 2.96 (d, J = 6.3 Hz, 2 H)
2.91 (d, J = 6.9 Hz, 2 H) 2.62 (q, J = 7.8 Hz, 2 H) 1.22 (t, J = 7.8 Hz, 3 H); ESI (m/z)
287(M+H+) 309(M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-ethylphenethyl) phenyl)-2-oxoethyl)
malonate (8a):
To a solution of NaH (0.7g, 19.3mmol) in THF (20mL), diethyl acetamidomalonate
(4.4 g, 20.1mmol) was added in portions at room temperature. The mixture was
stirred for a further 2h and a solution of 7a (4.6 g, 16.1 mmol) in THF was added. The
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mixture was heated at 70°C for further 12h and concentrated. The residue was diluted
with EtOAc(30mL), washed with brine, dried over Na2SO4, filtered and concentrated.
The residue was purified by silica gel flash column chromatography (EtOAc/PE) to
afford compound 8a (3.0g, 79.3% yield) as yellow syrup. 1H NMR (300 MHz CDCl3): δ 7.88 (d, J = 8.1 Hz, 2 H) 7.26-7.23 (m, 2 H) 7.16-7.06
(m, 4 H) 4.31-4.24 (m, 6 H) 2.96-2.92 (m, 4 H) 2.63 (q, J = 8.1 Hz, 2 H) 1.97 (s, 3 H)
1.33-1.20 (m, 9 H); ESI (m/z) 468 (M+H+) 490 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-ethylphenethyl)phenethyl)malonate
(9a):
A solution of 8a (1.6 g, 3.4 mmol) in CH2Cl2 (20mL) was added dropwise to a
solution of Et3SiH (1.5 g, 12.8 mmol) in CH2Cl2 at room temperature under Ar2
protection. TiCl4 (2.4 g, 12.8 mmol) was added with a syringe and the reaction
mixture was stirred for 12 h at room temperature. The solution was poured slowly into
ice water (20mL). The aqueous phase was extracted with CH2Cl2(5mL×3). The
combined organic layers were washed with brine, dried over Na2SO4, filtered and
concentrated, yielding crude product 9a (1.5g, 97.4% yield) as yellow oil.
ESI (m/z) 454 (M+H+) 476 (M+Na
+)
Synthesis of N-(4-(4-(4-ethylphenethyl)phenyl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)acetamide (10a):
To a solution of 9a (1.5 g, 3.4 mmol) in EtOH(20mL) was added K2HPO4 (6.1 g,
26.8 mmol) buffer and NaBH4 (0.66 g, 17.4 mmol), then stirred for 12 h at room
temperature. The solution was poured slowly into a mixture of saturated aq. NH4Cl
and EtOAc(20mL). The aqueous phase was extracted with EtOAc(5mL×3). The
combined organic layers were washed with brine, dried over Na2SO4, filtered and
concentrated. The residue was purified by silica gel flash column chromatography
(CH2Cl2/MeOH) to afford compound 10a (1.2g, 98.4% yield) as white solid.
mp: 32-34 oC;
1H NMR (300 MHz, CDCl3): δ 7.30-7.11 (m, 8 H) 5.89 (s, 1 H) 3.86 (d,
J = 11.7 Hz, 2 H) 3.62 (d, J = 11.7 Hz, 2 H) 2.87 (d, J = 7.5 Hz, 4 H) 2.66-2.58 (m, 4
H) 1.98-.93 (m, 4 H) 1.98-1.93 (m, 5 H) 1.22 (t, J = 7.5 Hz, 3 H); ESI (m/z) 370
(M+H+) 392 (M+Na+)
Synthesis of 2-amino-2-(4-(4-ethylphenethyl)phenethyl)propane-1,3-diol (11a):
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To a solution of 10a (0.11 g, 0.3 mmol) in MeOH(5mL) was added NaOH(0.01 g,
0.3 mmol) and heated for 8h at 80oC. The mixture was added HCl-EtOH solution until
pH=2-3 and concentrated. The residue was purified by silica gel flash column
chromatography (CH2Cl2/MeOH) to afford compound 11a (0.1g, 95% yield) as white
solid.
mp: 56-58 oC; 1H NMR (300 MHz, CD3OD): δ 7.09-7.01 (m, 8 H) 3.64 (brs, 4 H)
2.79 (brs, 4 H) 2.61-2.52 (m, 4 H) 1.92-1.86 (m, 2 H) 1.52 (t, J = 7.5 Hz, 3 H); 13C
NMR (100 MHz, CD3OD): δ 142.90, 141.12, 140.21, 139.77, 129.75, 129.46, 129.16,
128.68, 62.52, 62.05, 38.73, 34.70, 29.68, 29.44, 16.26; HRMS calcd. for
C21H30NO2 (M+H+) 328.2276, found 328.2278
Synthesis of benzyl (4-(4-(4-ethylphenethyl)phenyl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)carbamate (12a):
To a solution of 11a (100mg, 0.27mmol)in saturated aq. NaHCO3 and EtOAc
mixture(5mL) was added CbzCl(56mg, 0.33mmol). The mixture was stirred for 4h at
room temperature. The aqueous phase was extracted with EtOAc(2mL×3). The
combined organic layers were washed with brine, dried over Na2SO4, filtered and
concentrated. The residue was purified by silica gel flash column chromatography
(CH2Cl2/MeOH) to afford compound 12a (100mg, 54.2% yield) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.34-7.07 (m, 13 H) 5.35 (s, 1 H) 5.07 (s, 2 H) 3.88 (d,
J = 11.7 Hz, 2 H) 3.65 (d, J = 11.4 Hz, 2 H) 2.86 (d, J = 6.9 Hz, 4 H) 2.63-2.53 (m, 4
H) 1.88 (t, J = 8.4 Hz, 2 H) 1.22 (t, J = 7.8 Hz, 3 H); ESI (m/z) 462 (M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(4-(4-ethylphenethyl)
phenyl)-2-(hydroxymethyl)butan-2-yl)carbamate (13a):
To a solution of 12a(100mg, 0.22mmol) in CH2Cl2(5mL) was added
tetrabenzylpyrophosphate(142mg, 0.26mmol), silver(I) oxide(102mg, 0.44mmol) and
tetrahexylammonium iodide(212mg, 0.44mmol). After stirring at room temperature
under Ar2 protection for 20 h, the reaction mixture was filtered through celite to
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remove insoluble materials, and then the filtrate was concentrated. The residue was
purified by silica gel flash column chromatography (CH2Cl2/MeOH) to afford
compound 13a (60mg, 37.8% yield) as colorless oil. 1H NMR (300 MHz, CD3COCD3): δ 7.38-7.05 (m, 23 H) 6.16 (s, 1 H) 5.09-5.05 (m,
6 H) 4.37-4.23 (m, 2 H) 3.83-3.68 (m, 2 H) 2.87-2.78 (m, 4 H) 2.58 (q, J = 9.9 Hz, 4
H) 2.14-1.89 (m, 2 H) 1.17 (t, J = 7.8 Hz, 3 H); ESI (m/z) 721 (M+H+)
Synthesis of 2-amino-4-(4-(4-ethylphenethyl)phenyl)-2-(hydroxymethyl)butyl
dihydrogen phosphate (14a):
To a solution of 13a (60mg, 0.08mmol) in MeOH was added 10%Pd/C (600mg)
and stirred under H2 atm for 8h. The reaction mixture was filtered through celite to
remove Pd/C and concentrated to afford 14a (30mg, 92.1% yield) as white solid.
mp: 158-161 oC
;
1H NMR (300 MHz, CD3OD): δ 7.16-7.00 (m, 8 H) 3.86-3.75 (m, 2
H) 3.56 (dd, J = 11.1 Hz, 4.8 Hz, 2 H) 2.79 (d, J = 9.0 Hz, 4 H) 2.56-2.49 (m, 4 H)
1.82-1.72 (m, 2 H) 1.14 (t, J = 7.8 Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ 142.90,
141.12, 140.21, 139.77, 129.75, 129.46, 129.16, 128.68, 62.52, 62.05, 38.73, 34.70,
29.68, 29.44, 16.26; HRMS calcd. for C21H31NO5P (M+H+) 408.1934, found
408.1915
Synthesis of 2-chloro-1-(4-(4-propylphenethyl)phenyl)ethanone (7b)
7b was prepared using the same procedure as that described for compound 7a.
Yellow solid(5.4g, 17.5% yield).
mp: 17-19 oC;
1H NMR (300 MHz, CD3COCD3): δ 7.27-7.91 (m, 2 H) 7.41-7.38 (m,
2 H) 7.15-7.07 (m, 4 H) 4.98 (s, 2 H) 3.03-2.91 (m, 4 H) 2.53 (t, J = 7.2 Hz, 2 H)
1.63-1.55 (m, 2 H) 0.89 (t, J = 7.5 Hz, 3 H); ESI (m/z) 301 (M+H+) 323 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-oxo-2-(4-(4-propylphenethyl)phenyl)ethyl)
malonate (8b)
8b was prepared using the same procedure as that described for compound 8a.
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Yellow solid(2.8g, 33.3% yield).
mp: 33-35 oC;
1H NMR (300 MHz, CDCl3): δ 7.88-7.85 (m, 2 H) 7.26-7.23 (m, 2 H)
7.11-7.04 (m, 4 H) 4.30-4.23 (m, 6 H) 2.98-2.86 (m, 4 H) 2.55 (t, J = 7.5 Hz, 2 H)
2.04 (s, 3 H) 1.66-1.58 (m, 2 H) 1.26-1.22 (m, 6 H) 0.93 (t, J = 7.2 Hz, 3 H); ESI (m/z)
482 (M+H+) 504 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-propylphenethyl)phenethyl)malonate
(9b)
9b was prepared using the same procedure as that described for compound 9a.
Yellow oil(0.8g, 85.6% yield). 1H NMR (300 MHz, CDCl3): δ 7.30-7.04 (m, 8 H) 6.75 (s, 1 H) 4.32-4.11 (m, 4 H)
2.89-2.77 (m, 4 H) 2.73-2.38 (m, 6 H) 2.05 (s, 3 H) 1.66-1.59 (m, 2 H) 1.38-1.21 (m,
6 H) 0.93 (t, J = 7.5 Hz, 3 H); ESI (m/z) 468 (M+H+) 490 (M+Na
+)
Synthesis of N-(1-hydroxy-2-(hydroxymethyl)-4-(4-(4-propylphenethyl)phenyl)
butan-2-yl)acetamide (10b)
10b was prepared using the same procedure as that described for compound 10a.
White solid(0.36g, 31.3% yield).
mp: 48-50 oC;
1H NMR (300 MHz, CDCl3): δ 7.12 (s, 4 H) 7.09 (s, 4 H) 5.82 (s, 1 H)
3.86 (d, J = 11.7 Hz, 2 H) 3.62 (d, J = 11.4 Hz, 2 H) 2.86 (s, 4 H) 2.63 (t, J = 7.8 Hz,
2 H) 1.55 (t, J = 7.2 Hz, 2 H) 1.97 (s, 3 H) 1.98-1.94 (m, 2 H) 1.66-1.59 (m, 2 H) 0.93
(t, J = 7.2 Hz, 3 H); ESI (m/z) 384 (M+H+) 406 (M+Na
+)
Synthesis of 2-amino-2-(4-(4-propylphenethyl)phenethyl)propane-1,3-diol (11b)
11b was prepared using the same procedure as that described for compound 11a.
White solid(0.27g, 79.6% yield).
mp: 155-158 oC;
1H NMR (300 MHz, CD3OD): δ 7.08-7.01 (q, 4 H) 6.98 (s, 4 H)
3.62 (s, 4 H) 2.77 (s, 4 H) 2.59-2.53 (m, 2 H) 2.47 (t, J = 7.8 Hz, 2 H) 1.90-1.84 (m, 2
H) 1.58-1.48 (m, 2 H) 0.86 (t, J = 7.5 Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ
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141.16, 140.25, 139.75, 129.77, 129.38, 129.35, 129.15, 62.54, 62.06, 38.76, 38.67,
34.72, 29.69, 25.81, 14.06; HRMS calcd. for C22H32NO2 (M+H+) 342.2433, found
342.2430
Synthesis of benzyl (1-hydroxy-2-(hydroxymethyl)-4-(4-(4-propylphenethyl)
phenyl)butan-2-yl)carbamate (12b)
12b was prepared using the same procedure as that described for compound 12a.
Colorless oil(117mg, 65.8% yield). 1H NMR (300 MHz, CDCl3): δ 7.36 (s, 4 H) 7.09 (brs, 9 H) 5.28 (s, 1 H) 5.09 (s, 2 H)
3.91 (d, J = 12.0 Hz, 2 H) 3.67 (d, J = 11.1 Hz, 2 H) 2.85 (s, 4 H) 2.57 (q, J = 9.3 Hz,
4 H) 1.89 (t, J = 7.8 Hz, 2 H) 1.66-1.59 (m, 2 H) 0.93 (t, J = 7.2 Hz, 3 H); ESI (m/z)
476(M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-2-(hydroxymethyl)
-4-(4-(4-propylphenethyl)phenyl)butan-2-yl)carbamate(13b)
13b was prepared using the same procedure as that described for compound 13a.
Colorless oil(61mg, 33.2% yield). 1H NMR (300 MHz, CDCl3): δ 7.35-7.28 (m, 15 H) 7.10-7.00 (m, 8 H) 5.11-4.97 (m,
6 H) 4.17-4.03 (m, 2 H) 3.69 (d, J = 11.1 Hz, 2 H) 2.85 (s, 4 H) 2.58-2.41 (m, 4 H)
2.15-2.05 (m, 1 H) 1.81-1.56 (m, 3 H) 0.93 (t, J = 6.9 Hz, 3 H); ESI (m/z) 736(M+H+)
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4-(4-propylphenethyl)phenyl)butyl
dihydrogen phosphate (14b)
14b was prepared using the same procedure as that described for compound 14a.
White solid(30mg, 88.2% yield).
mp: 180-183 oC
;
1H NMR (300 MHz, CD3OD): δ 8.13-7.82 (m, 2 H) 7.49-7.03 (m, 6
H) 4.00 (brs, 2 H) 3.69 (brs, 2 H) 3.07-2.49 (m, 8 H) 1.98-1.93 (m, 2 H) 1.70-1.56 (m,
2 H) 0.91 (t, J = 6.9 Hz, 3 H); 13
C NMR (100 MHz, CD3OD) δ 141.20, 141.12,
140.28, 139.68, 129.74, 129.39, 129.34, 129.22, 65.83, 62.50, 61.41, 38.77, 38.67,
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34.88, 29.62, 25.82, 14.06 HRMS calcd. for C22H32NO5P(M+H+) 422.2091, found
422.2050
Synthesis of 1-(4-(4-butylphenethyl)phenyl)-2-chloroethanone (7c)
7c was prepared using the same procedure as that described for compound 7a.
Yellow solid(8.1g, 26.1% yield).
mp: 22-25 oC;
1H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 2 H) 7.28 (d, J =
7.8 Hz, 2 H) 7.08 (dd, J = 12.0 Hz, 8.7 Hz, 4 H) 4.69 (s, 2 H) 3.00-2.86 (m, 4 H) 2.57
(t, J = 7.8 Hz, 2 H) 1.60-1.53 (m, 2 H) 1.38-1.31 (m, 2 H) 0.92 (t, J = 7.2 Hz, 3 H);
ESI (m/z) 315 (M+H+) 337 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-butylphenethyl)phenyl)-2-oxoethyl)
malonate (8c)
8c was prepared using the same procedure as that described for compound 8a.
Yellow syrup(2.4g, 53.2% yield). 1H NMR (300 MHz, CDCl3): δ 7.87 (d, J = 7.8 Hz, 2 H) 7.25 (d, J = 7.2 Hz, 2 H)
7.11-7.05 (m, 4 H) 4.31-4.20 (m, 6 H) 3.00-2.86 (m, 4 H) 2.58 (t, J = 7.8 Hz, 2 H)
1.97 (s, 3 H) 1.64-1.56 (m, 2 H) 1.42-1.29 (m, 2 H) 1.25 (t, J = 7.2 Hz, 6 H) 0.93 (t, J
= 7.2 Hz, 3 H); ESI (m/z) 496 (M+H+) 518 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-butylphenethyl)phenethyl)malonate (9c)
9c was prepared using the same procedure as that described for compound 9a.
Crude prodct as yellow oil(1.3g, 98.2% yield).
ESI (m/z) 482(M+H+) 504 (M+Na
+)
Synthesis of N-(4-(4-(4-butylphenethyl)phenyl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)acetamide (10c)
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10c was prepared using the same procedure as that described for compound 10a.
White solid(1.0g, 94.3% yield).
mp: 53-54 oC;
1H NMR (300 MHz, CDCl3): δ 7.12-7.09 (m, 8 H) 5.89 (s, 1 H) 3.86 (d,
J = 11.7 Hz, 2 H) 3.62 (d, J = 11.7 Hz, 2 H) 2.86 (brs, 4 H) 2.66-2.58 (m, 4 H)
1.98-1.93 (m, 5 H) 1.63-1.53 (m, 2 H) 1.38-1.29 (m, 2 H) 0.92 (t, J = 7.5 Hz, 3 H);
ESI (m/z) 398 (M+H+) 420 (M+Na
+)
Synthesis of 2-amino-2-(4-(4-butylphenethyl)phenethyl)propane-1,3-diol (11c)
11c was prepared using the same procedure as that described for compound 11a.
White solid(0.3g, 76.7% yield).
mp: 134-137 oC;
1H NMR (300 MHz, CD3OD): δ 7.07 (d, J = 7.8 Hz, 2 H) 7.03 (d, J
= 8.1 Hz, 2 H) 6.98 (brs, 4 H) 3.63 (brs, 4 H) 2.78 (brs, 4 H) 2.60-2.47 (m, 4 H)
1.91-1.85 (m, 2 H) 1.56-1.46 (m, 2 H) 1.34-1.25 (m, 2 H) 0.87 (t, J = 7.5 Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ 141.42, 141.13, 140.20, 139.77, 129.75, 129.39,
129.27, 129.15, 62.53, 62.05, 38.75, 36.22, 35.03, 34.70, 29.68, 23.32, 14.28; HRMS
calcd. for C23H34NO2 (M+H+) 356.2589, found 356.2595
Synthesis of benzyl (4-(4-(4-butylphenethyl)phenyl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)carbamate (12c)
12c was prepared using the same procedure as that described for compound 12a.
Colorless oil(80mg, 64.0% yield). 1H NMR (300 MHz, CDCl3): δ 7.36 (brs, 5 H) 7.19-7.10 (m, 8 H) 5.32 (brs, 1 H) 5.09
(s, 2 H) 3.91 (d, J = 12.0 Hz, 2 H) 3.67 (d, J = 11.7 Hz, 2 H) 2.86 (brs, 4 H) 2.58 (t, J
= 8.1 Hz, 4 H) 1.90 (t, J = 9.0 Hz, 2 H) 1.62-1.54 (m, 2 H) 1.39-1.32 (m, 2 H) 0.93 (t,
J = 7.5 Hz, 3 H); ESI (m/z) 490(M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(4-(4-butylphenethyl)
phenyl)-2-(hydroxymethyl)butan-2-yl)carbamate (13c)
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13c was prepared using the same procedure as that described for compound 13a.
Colorless oil(40mg, 33.4% yield). 1H NMR (300 MHz, CDCl3): δ 7.31-7.07 (m, 23 H) 5.27-4.98 (m, 6 H) 4.11-4.08 (m,
2 H) 3.70-3.68 (m, 2 H) 2.83 (brs, 4 H) 2.55 (t, J = 8.1 Hz, 4 H) 1.62-1.54 (m, 2 H)
1.26-1.19 (m, 4 H) 0.90 (t, J = 6.0 Hz, 3 H); ESI (m/z) 750(M+H+)
Synthesis of 2-amino-4-(4-(4-butylphenethyl)phenyl)-2-(hydroxymethyl)butyl
dihydrogen phosphate (14c)
14c was prepared using the same procedure as that described for compound 14a.
White solid(18mg, 82.8% yield).
mp: 182-185 oC
;
1H NMR (300 MHz, CD3OD): δ 7.16-6.98 (m, 8 H) 3.93 (t, J = 6.3
Hz, 2 H) 3.66 (dd, J = 12.9 Hz, 6.9 Hz, 3 H) 2.77 (brs, 4 H) 2.63-2.47 (m, 4 H)
1.95-1.81 (m, 2 H) 1.53-1.45 (m, 2 H) 1.34-1.25 (m, 2 H) 0.86 (t, J = 7.2 Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ 141.42, 141.13, 140.20, 139.77, 129.75, 129.39,
129.27, 129.15, 62.53, 62.05, 38.75, 36.22, 35.03, 34.70, 29.68, 23.32, 14.28; HRMS
calcd. for C23H35NO5P (M+H+) 436.2247, found 436.2233
Synthesis of 2-chloro-1-(4-(3-(4-ethylphenyl)propyl)phenyl)ethanone (7d)
7d was prepared using the same procedure as that described for compound 7a.
White solid(7.1g, 23.8% yield).
mp: 18-20 oC;
1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 2 H) 7.30 (d, J =
8.4 Hz, 2 H) 7.11 (dd, J = 12.3 Hz, 8.4 Hz, 4 H) 4.69 (s, 2 H) 2.71 (t, J = 7.5 Hz, 2 H)
2.66-2.58 (m, 4 H) 2.01-1.91 (m, 2 H) 1.22 (t, J = 7.5 Hz, 3 H); ESI (m/z) 301 (M+H+)
323 (M+Na+)
Synthesis of diethyl 2-acetamido-2-(2-(4-(3-(4-ethylphenyl)propyl)phenyl)
-2-oxoethyl)malonate (8d)
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8d was prepared using the same procedure as that described for compound 8a.
Yellow solid(4.0g, 37.6% yield).
mp: 31-34 oC;
1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 8.4 Hz, 2 H) 7.27 (d, J =
8.4 Hz, 2 H) 7.14-7.07 (m, 4 H) 4.30-4.23 (m, 6 H) 2.69 (t, J = 7.2 Hz, 2 H) 2.66-2.58
(m, 4 H) 1.96 (s, 3 H) 2.00-1.89 (m, 2 H) 1.29-1.18 (m, 9 H); ESI (m/z) 482 (M+H+)
504 (M+Na+)
Synthesis of diethyl 2-acetamido-2-(4-(3-(4-ethylphenyl)propyl)phenethyl)
malonate (9d)
9d was prepared using the same procedure as that described for compound 9a.
Yellow oil(2.1g, 89.9% yield). 1H NMR (300 MHz, CDCl3): δ 7.27-7.03 (m, 8 H) 6.76 (s, 1 H) 4.29-4.11 (m, 4 H)
2.87-2.57 (m, 8 H) 2.44 (d, J = 6.9 Hz, 2 H) 1.99 (s, 3 H) 2.10-1.91 (m, 2 H)
1.31-1.17 (m, 9 H); ESI (m/z) 468 (M+H+) 490 (M+Na
+)
Synthesis of N-(4-(4-(3-(4-ethylphenyl)propyl)phenyl)-1-hydroxy-2-
(hydroxymethyl)butan-2-yl)acetamide (10d)
10d was prepared using the same procedure as that described for compound 10a.
White solid(1.2g, 44.8% yield).
mp: 42-44oC;
1H NMR (300 MHz, CDCl3): δ 7.25 (s, 4 H) 7.11 (s, 4 H) 5.82 (s, 1 H)
3.86 (d, J = 11.1 Hz, 2 H) 3.74 (s, 2 H) 3.62 (d, J = 11.1 Hz, 2 H) 2.65-2.58 (q, 8 H)
1.94 (s, 3 H) 2.06-1.86 (m, 2 H) 1.67-1.60 (m, 2 H) 1.31-1.19 (m, 3 H); ESI (m/z)
384 (M+H+) 406 (M+Na
+)
Synthesis of 2-amino-2-(4-(3-(4-ethylphenyl)propyl)phenethyl)propane-1,3-diol
(11d)
11d was prepared using the same procedure as that described for compound 11a.
White solid(0.75g, 73.3% yield).
mp: 55-57 oC;
1H NMR (300 MHz, CD3OD): δ 7.10-7.01 (m, 8 H) 3.62 (s, 4 H)
2.60-2.48 (m, 8 H) 1.91-1.81 (m, 4 H) 1.14 (t, J = 7.5 Hz, 3 H); 13
C NMR (100 MHz,
CD3OD): δ 142.80, 141.58, 140.71, 139.68, 129.67, 129.38, 129.23, 128.74, 62.53,
62.05, 35.98, 35.97, 34.74, 34.67, 29.69, 29.45, 16.28; HRMS calcd. for C22H32NO2
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(M+H+) 342.2433, found 342.2433
Synthesis of benzyl (4-(4-(3-(4-ethylphenyl)propyl)phenyl)-1-hydroxy-2-
(hydroxymethyl)butan-2-yl)carbamate (12d)
12d was prepared using the same procedure as that described for compound 12a.
Colorless oil(70mg, 66.9% yield). 1H NMR (300 MHz, CD3COCD3): δ 7.38-7.25 (m, 8 H) 7.09-7.07 (m, 7 H) 5.04 (s, 2
H) 3.79 (d, J = 11.1 Hz, 2 H) 3.68 (d, J = 11.1 Hz, 2 H) 2.62-2.53 (m, 8 H) 2.03-1.86
(m, 4 H) 1.16 (t, J = 7.5 Hz, 3 H); ESI (m/z) 476 (M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(4-(3-(4-ethylphenyl)
propyl)phenyl)-2-(hydroxymethyl)butan-2-yl)carbamate (13d)
13d was prepared using the same procedure as that described for compound 13a.
Colorless oil(40mg, 36.3% yield). 1H NMR (300 MHz, CD3COCD3): δ 7.37-7.24 (m, 15 H) 7.10-7.08 (m, 8 H)
5.08-5.04 (m, 6 H) 4.37-4.22 (m, 2 H) 3.74 (q, J = 11.1 Hz, 2 H) 2.61-2.54 (m, 8 H)
2.05-1.86 (m, 4 H) 1.17 (t, J = 7.5 Hz, 3 H); ESI (m/z) 736 (M+H+)
Synthesis of 2-amino-4-(4-(3-(4-ethylphenyl)propyl)phenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (14d)
14d was prepared using the same procedure as that described for compound 14a.
White solid(18mg, 79.2% yield).
mp: 155-158 oC
;
1H NMR (300 Hz, CD3OD): δ 7.09-7.02 (m, 8 H) 3.93 (brs, 2 H)
3.64 (brs, 2 H) 2.62-2.53 (m, 8 H) 1.85-1.83 (m, 4 H) 1.15 (t, J = 7.8 Hz, 3 H); 13
C
NMR (100 MHz, CD3OD): δ 142.79, 141.50, 140.74, 139.76, 129.63, 129.40, 129.31,
128.74, 65.92, 62.76, 61.13, 61.09, 35.98, 35.12, 34.67, 30.75, 29.64, 29.46, 16.29;
HRMS calcd. for C22H33NO5P (M+H+) 422.2091, found 422.2084
Synthesis of 2-chloro-1-(4-(4-(4-isopropylphenyl)butyl)phenyl)ethanone (7e)
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7e was prepared using the same procedure as that described for compound 7a.
Crude product as yellow oil(14g, 93.3% yield).
ESI (m/z) 329 (M+H+); 351(M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-(4-isopropylphenyl)butyl)phenyl)
-2-oxoethyl)malonate (8e)
8e was prepared using the same procedure as that described for compound 8a.
Yellow solid(4g, 19.9% yield).
mp: 26-28 oC;
1H NMR (300 MHz, CDCl3): δ 7.87 (d, J = 6.0 Hz, 2 H) 7.24 (d, J =
6.0 Hz, 2 H) 7.13 (d, J = 6.0 Hz, 1 H) 7.08 (t, J = 8.4 Hz, 2 H) 4.29-4.23 (q, 6 H)
2.88-2.85 (m, 1 H) 2.68 (t, J = 4.8 Hz, 2 H) 2.59 (t, J = 5.4 Hz, 2 H) 1.96 (s, 3 H)
1.67-1.63 (m, 4 H) 1.23 (t, J = 5.1 Hz, 12 H); ESI (m/z) 510 (M+H+) 532 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(4-isopropylphenyl)butyl)phenethyl)
malonate (9e)
9e was prepared using the same procedure as that described for compound 9a.
Crude product as yellow oil(2.0g, 98.0% yield).
ESI (m/z) 496 (M+H+); 518(M+Na
+)
Synthesis of N-(1-hydroxy-2-(hydroxymethyl)-4-(4-(4-(4-isopropylphenyl)butyl)
phenyl)butan-2-yl)acetamide (10e)
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10e was prepared using the same procedure as that described for compound 10a.
White solid(0.3g, 14.3% yield).
mp: 28-30 oC;
1H NMR (300 MHz, CDCl3): δ 7.25 (s, 4 H) 7.14-7.06 (q, 4 H) 5.77 (s,
1 H) 3.87 (d, J = 11.4 Hz, 2 H) 3.68 (s, 2 H) 3.62 (d, J = 11.7 Hz, 2 H) 2.91-2.82 (m, 1
H) 2.65-2.59 (m, 6 H) 1.93 (s, 3 H) 1.98-1.95 (m, 2 H) 1.63 (brs, 4 H) 1.23 (d, J = 7.2
Hz, 6 H); ESI (m/z) 412 (M+H+) 434 (M+Na
+)
Synthesis of 2-amino-2-(4-(4-(4-isopropylphenyl)butyl)phenethyl)propane-1,3-
diol (11e)
11e was prepared using the same procedure as that described for compound 11a.
White solid(0.11g, 42.2% yield).
mp: 160-162 oC;
1H NMR (300 MHz, CD3OD): δ 7.08-6.97 (m, 8 H) 3.62 (s, 4 H)
2.80-2.76 (m, 1 H) 2.59-2.51 (m, 6 H) 1.90-1.84 (m, 2 H) 1.54 (brs, 4 H) 1.16 (d, J =
6.9 Hz, 6 H); 13
C NMR (100 MHz, CD3OD): δ 147.34, 141.78, 141.10, 139.58,
129.63, 129.32, 129.17, 127.20, 62.53, 62.04, 36.28, 34.99, 34.75, 32.29, 29.67, 24.53;
HRMS calcd. for C24H36NO2 (M+H+) 370.2746, found 370.2743
Synthesis of benzyl (1-hydroxy-2-(hydroxymethyl)-4-(4-(4-(4-isopropylphenyl)
butyl)phenyl)butan-2-yl)carbamate (12e)
12e was prepared using the same procedure as that described for compound 12a.
Colorless oil(70mg, 69.6% yield). 1H NMR (300 MHz, CDCl3): δ 7.35-7.01 (m, 13 H) 5.07 (s, 2 H) 3.88 (d, J = 11.4 Hz,
2 H) 3.66 (d, J = 11.4 Hz, 2 H) 2.88-2.84 (m, 1 H) 2.58-2.47 (m, 6 H) 1.89 (t, J = 8.7
Hz, 2 H) 1.63 (brs, 4 H) 1.23 (d, J = 7.2 Hz, 6 H); ESI (m/z) 504 (M+H+);
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-2-(hydroxymethyl)-4-
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(4-(4-(4-isopropylphenyl)butyl)phenyl)butan-2-yl)carbamate (13e)
13e was prepared using the same procedure as that described for compound 13a.
Crude product as colorless oil(30mg, 28.0% yield).
ESI (m/z) 764 (M+H+);
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4-(4-(4-isopropylphenyl)butyl)phenyl)
butyl dihydrogen phosphate (14e)
14e was prepared using the same procedure as that described for compound 14a.
White solid(12mg, 68.5% yield).
mp: 145-148 oC
;
1H NMR (300 MHz, CD3OD) δ 7.09-6.97 (m, 8 H) 3.93-3.84 (m, 2
H) 3.63 (dd, J = 15.3 Hz, 8.4 Hz, 2 H) 2.80-2.73 (m, 1 H) 2.61-2.51 (m, 6 H)
1.90-1.86 (m, 2 H) 1.54 (brs, 4 H) 1.15 (d, J = 6.9 Hz, 6 H); 13
C NMR (100 MHz,
CD3OD): δ 147.32, 141.71, 141.12, 139.61, 129.59, 129.32, 129.24, 127.20, 65.87,
62.64, 61.20, 36.39, 35.01, 32.31, 29.62, 24.53; HRMS calcd. for C24H37NO5P (M+H+)
450.2404, found 450.2403
Synthesis of 2-chloro-1-(6-hexylnaphthalen-2-yl)ethanone (7f)
7f was prepared using the same procedure as that described for compound 7a.
Yellow oil(6.0g, 23.9% yield).
1H NMR (300 MHz, CDCl3): δ 8.43 (s, 1 H) 8.02-7.73 (m, 3 H) 7.65 (s, 1 H)
7.50-7.41 (q, 1 H) 4.79 (s, 2 H) 3.09 (t, J = 7.8 Hz, 2 H) 1.73-1.68 (m, 2 H) 1.32 (brs,
6 H) 0.88 (t, J = 6.3 Hz, 3 H); ESI (m/z) 289 (M+H+) 311 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(6-hexylnaphthalen-2-yl)-2-oxoethyl)
malonate (8f)
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8f was prepared using the same procedure as that described for compound 8a.
Yellow oil(3.4g, 17.9% yield). 1H NMR (300 MHz, CDCl3): δ 8.48 (s, 1 H) 7.99-7.73 (m, 3 H) 7.63 (s, 1 H) 7.42 (d,
J = 8.1 Hz, 1 H) 7.15 (s, 1 H) 4.39-4.25 (m, 6 H) 2.79 (t, J = 7.2 Hz, 2 H) 1.97 (s, 3 H)
1.73-1.67 (m, 2 H) 1.32-1.23 (m, 12 H) 0.96 (t, J = 4.5 Hz, 3 H); ESI (m/z) 470
(M+H+) 492 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(6-hexylnaphthalen-2-yl)ethyl)malonate
(9f)
9f was prepared using the same procedure as that described for compound 9a.
Yellow oil(0.8g, 33.2% yield). 1H NMR (300 MHz, CDCl3): δ 7.67 (d, J = 7.8 Hz, 2 H) 7.54 (s, 2 H) 7.31-7.22 (m, 2
H) 6.79 (s, 1 H) 4.25-4.14 (m, 4 H) 2.80-2.71 (m, 4 H) 2.65-2.60 (m, 2 H) 1.97 (s, 3 H)
1.70-1.65 (m, 2 H) 1.31-1.20 (m, 12 H) 0.87 (t, J = 7.2 Hz, 3 H); ESI (m/z) 456
(M+H+) 478 (M+Na
+)
Synthesis of N-(4-(6-hexylnaphthalen-2-yl)-1-hydroxy-2-(hydroxymethyl)butan-2
-yl)acetamide (10f)
10f was prepared using the same procedure as that described for compound 10a.
White sollid(1.1g, 71.9% yield).
mp: 50-51 oC;
1H NMR (300 MHz, CDCl3): δ 7.69 (t, J = 8.4 Hz, 2 H) 7.57 (d, J = 9.3
Hz, 2 H) 7.31 (d, J = 8.7 Hz, 2 H) 5.87 (s, 1 H) 3.91 (d, J = 10.2 Hz, 2 H) 3.72 (s, 2 H)
3.65 (d, J = 12.3 Hz, 2 H) 2.83-2.72 (m, 4 H) 2.08-1.94 (m, 2 H) 1.93 (s, 3 H) 1.66 (t,
J = 6.6 Hz, 2 H) 1.31 (brs, 6 H,) 0.87 (brs, 3 H); ESI (m/z) 372 (M+H+) 394 (M+Na
+)
Synthesis of 2-amino-2-(2-(6-hexylnaphthalen-2-yl)ethyl)propane-1,3-diol (11f)
11f was prepared using the same procedure as that described for compound 11a.
White sollid(0.58g, 60.9% yield).
mp: 175-178 oC;
1H NMR (300 MHz, CD3OD): δ 7.65 (t, J = 7.8 Hz, 2 H) 7.58 (s, 1
H) 7.51 (s, 1 H) 7.31-7.24 (m, 2 H) 3.67 (s, 4 H) 2.79-2.66 (m, 4 H) 2.02-1.96 (m, 2 H)
1.89-1.83 (m, 2 H) 1.28 (brs, 6 H) 0.85-0.81 (m, 3 H); 13
C NMR (100 MHz, CD3OD):
δ 141.14, 139.00, 133.86, 133.65, 128.73, 128.58, 128.36, 127.93, 127.10, 127.08,
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62.56, 62.12, 37.00, 34.56, 32.89, 32.56, 30.20, 30.07, 23.67, 14.40; HRMS calcd. for
C21H32NO2 (M+H+) 330.2427, found 330.2424
Synthesis of benzyl (4-(6-hexylnaphthalen-2-yl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)carbamate (12f)
12f was prepared using the same procedure as that described for compound 12a.
Colorless oil(110mg, 79.2% yield). 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, J = 7.5 Hz, 5.4 Hz, 2 H) 7.54 (s, 2 H)
7.34-7.25 (m, 7 H) 5.07 (s, 2 H) 3.94 (d, J = 11.1 Hz, 2 H) 3.70 (d, J = 11.4 Hz, 2 H)
2.76-2.73 (m, 4 H) 1.98 (t, J = 8.4 Hz, 2 H) 1.68-1.65 (m, 2 H) 1.31 (brs, 6 H) 0.87
(brs, 3 H); ESI (m/z) 464(M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(6-hexylnaphthalen-2
-yl)-2-(hydroxymethyl)butan-2-yl)carbamate (13f)
13f was prepared using the same procedure as that described for compound 13a.
Colorless oil(70mg, 40.3% yield). 1H NMR (300 MHz, CDCl3) δ 7.67-7.19 (m, 21 H) 5.11-5.00 (m, 6 H) 4.16-3.69 (m, 4
H) 2.74 (t, J = 7.2 Hz, 4 H) 2.02-1.66 (m, 4 H) 1.31 (brs, 6 H) 0.88 (brs, 3 H); ESI
(m/z) 724(M+H+)
Synthesis of 2-amino-4-(6-hexylnaphthalen-2-yl)-2-(hydroxymethyl)butyl
dihydrogen phosphate (14f)
14f was prepared using the same procedure as that described for compound 14a.
White solid(38mg, 95.8% yield).
mp: 118-120 oC
;
1H NMR (300 MHz, CD3OD) δ 7.66-7.21 (m, 6 H) 4.08-3.64 (m, 4
H) 2.68 (t, J = 7.5 Hz, 4 H) 2.08-2.05 (m, 2 H) 1.64-1.61 (m, 2 H) 1.28 (brs, 6 H) 0.84
(brs, 3 H); 13
C NMR (100 MHz, CD3OD): δ141.14, 139.00, 133.86, 133.65, 128.73,
128.58, 128.36, 127.93, 127.10, 127.08, 67.10, 63.21, 60.44, 37.04, 33.66, 32.91,
32.60, 30.54, 30.11, 23.69, 14.41; HRMS calcd. for C21H33NO5P (M+H+) 410.2091,
found 410.2085
Synthesis of 2-chloro-1-(6-hexylnaphthalen-1-yl)ethanone (7g)
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22
7g was prepared using the same procedure as that described for compound 7a.
Yellow oil(15.9g, 63.5%). 1H NMR (300 MHz, CDCl3): δ 8.55 (d, J = 7.8 Hz, 1 H) 7.83-7.81 (m, 2 H) 7.70 (s, 1
H) 7.58-7.50 (m, 2 H) 4.78 (s, 2 H) 2.80 (t, J = 7.5 Hz, 2 H) 1.74-1.66 (m, 2 H) 1.33
(brs, 6 H) 0.89 (t, J = 6.3 Hz, 3 H); ESI (m/z) 289 (M+H+) 311 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(6-hexylnaphthalen-1-yl)-2-oxoethyl)
malonate (8g)
8g was prepared using the same procedure as that described for compound 8a.
Yellow oil(2.4g, 12.6%). 1H NMR (300 MHz, CDCl3): δ 8.63 (d, J = 9.0 Hz, 1 H) 7.84-7.78 (m, 2 H) 7.50 (t, J
= 4.5 Hz, 1 H) 7.30-7.08 (m, 2 H) 7.02 (s, 1 H) 4.37-4.30 (m, 6 H) 2.82-2.59 (m, 2 H)
2.00 (s, 3 H) 1.67 (brs, 2 H) 1.33-1.25 (m, 12 H) 0.89 (brs, 3 H); ESI (m/z) 470
(M+H+) 492 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(6-hexylnaphthalen-1-yl)ethyl)malonate
(9g)
9g was prepared using the same procedure as that described for compound 9a.
Yellow oil(0.9g, 37.3% yield). 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 1 H) 7.66 (m, 2 H) 7.33-7.23 (m,
3 H) 6.91 (s, 1 H) 4.31-4.10 (m, 4 H) 2.95-2.91 (m, 2 H) 2.85-2.74 (m, 4 H) 2.07 (s, 3
H) 1.72-1.65 (m, 2 H) 1.33-1.25 (m, 6 H) 1.22 (t, J = 7.2 Hz, 6 H) 0.88 (t, J = 6.9 Hz,
3 H); ESI (m/z) 456 (M+H+) 478 (M+Na
+)
Synthesis of N-(4-(6-hexylnaphthalen-1-yl)-1-hydroxy-2-(hydroxymethyl)butan
-2-yl)acetamide (10g)
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10g was prepared using the same procedure as that described for compound 10a.
Yellow oil(0.4g, 19.3%). 1H NMR (300 MHz, CDCl3): δ 7.81-7.66 (m, 3 H) 7.35-7.30 (m, 3 H) 5.93 (s, 1 H)
3.96 (d, J = 11.4 Hz, 2 H) 3.65 (d, J = 11.7 Hz, 2 H) 3.10 (t, J = 8.1 Hz, 2 H) 2.80 (t, J
= 7.5 Hz, 2 H) 2.08 (t, J = 8.4 Hz, 2 H) 1.98 (s, 3 H) 1.76-1.68 (m, 2 H) 1.33-1.25 (m,
6 H) 0.89 (brs, 3 H); ESI (m/z) 372 (M+H+) 394 (M+Na
+)
Synthesis of 2-amino-2-(2-(6-hexylnaphthalen-1-yl)ethyl)propane-1,3-diol (11g)
11g was prepared using the same procedure as that described for compound 11a.
White solid(0.25g, 69.4%).
mp: 140-142 oC;
1H NMR (300 MHz, CD3OD): δ 7.86 (s, 1 H) 7.71 (d, J = 8.7 Hz, 1
H) 7.63-7.60 (m, 1 H) 7.28-7.23 (m, 3 H) 3.75 (s, 4 H) 3.11-3.05 (m, 2 H) 2.75 (t, J =
7.5 Hz, 2 H) 2.05-1.99 (m, 2 H) 1.69-1.62 (m, 2 H) 1.29 (brs, 6 H) 0.84 (t, J = 6.6 Hz,
3 H); 13
C NMR (100 MHz, CD3OD): δ 141.91, 137.85, 133.94, 133.10, 129.76,
128.04, 127.82, 127.05, 125.78, 123.18, 62.61, 62.19, 37.50, 33.84, 32.94, 32.78,
30.25, 27.46, 23.71, 14.43; HRMS calcd. for C21H32NO2 (M+H+) 330.2427, found
330.2428
Synthesis of benzyl (4-(6-hexylnaphthalen-1-yl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)carbamate (12g)
12g was prepared using the same procedure as that described for compound 12a.
Colorless oil(90mg, 94.1%). 1H NMR (300 MHz, CD3COCD3): δ 8.06 (s, 1 H) 7.77 (d, J = 8.7 Hz, 1 H) 7.68-7.62
(m, 1 H) 7.42-7.28 (m, 8 H) 5.11 (s, 2 H) 3.90 (d, J = 10.8 Hz, 2 H) 3.77 (d, J = 10.8
Hz, 2 H) 3.15-3.09 (m, 2 H) 2.16-2.02 (m, 4 H) 1.72-1.69 (m, 2 H) 1.33 (brs, 6 H)
0.85 (t, J = 6.6 Hz, 3 H); ESI (m/z) 464(M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(6-hexylnaphthalen
-1-yl)-2-(hydroxymethyl)butan-2-yl)carbamate (13g)
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13g was prepared using the same procedure as that described for compound 13a.
Colorless oil(50mg, 43.2% yield). 1H NMR (300 MHz, CD3COCD3): δ 8.02 (s, 1 H) 7.79 (d, J = 8.4 Hz, 1 H) 7.68 (dd, J
= 7.2 Hz, 2.7 Hz, 1 H) 7.39-7.28 (m, 18 H) 5.17-5.03 (m, 6 H) 4.42 (dd, J = 10.2 Hz,
6.6 Hz, 1 H) 4.30 (dd, J = 10.2 Hz, 6.6 Hz, 1 H) 3.86 (q, J = 11.4 Hz, 2 H) 3.11 (dd, J
= 9.9 Hz, 8.1 Hz, 2 H) 2.78 (t, J = 7.8 Hz, 2 H) 2.62-2.05 (m, 2 H) 1.73-1.65 (m, 2 H)
1.31-1.26 (m, 6 H) 0.83 (t, J = 7.2 Hz, 3 H); ESI (m/z) 724(M+H+)
Synthesis of 2-amino-4-(6-hexylnaphthalen-1-yl)-2-(hydroxymethyl)butyl
dihydrogen phosphate (14g)
14g was prepared using the same procedure as that described for compound 14a.
White syrup(20mg, 69.8%). 1H NMR (300 MHz, CD3OD): δ 7.80 (s, 1 H) 7.67 (d, J = 8.4 Hz, 1 H) 7.57 (d, J =
7.5 Hz, 1 H) 7.26-7.23 (m, 3 H) 4.05 (brs, 2 H) 3.76 (brs, 2 H) 3.06 (brs, 2 H) 2.73 (t,
J = 7.2 Hz, 2 H) 2.05-1.99 (m, 2 H) 1.69-1.62 (m, 2 H) 1.26 (brs, 6 H) 0.81 (t, J = 6.6
Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ 142.05, 137.68, 133.91, 133.12, 129.75,
128.01, 127.82, 127.11, 125.80, 123.15, 66.13, 62.43, 61.05, 37.51, 33.86, 32.98,
32.89, 30.28, 27.20, 23.72, 14.43; HRMS calcd. for C21H33NO5P (M+H+) 410.2091,
found 410.2093
Synthesis of 2-chloro-1-(2-hexylchroman-6-yl)ethanone (7h)
7h was prepared using the same procedure as that described for compound 7a.
Yellow solid(7.6g, 90.1%).
mp: 25-27 oC;
1H NMR (300 MHz, CDCl3): δ 7.72-7.69 (m, 2 H) 6.85 (d, J = 8.7 Hz,
1 H) 4.64 (s, 2 H) 4.11-4.06 (m, 1 H) 2.93-2.77 (m, 2 H) 2.07-1.19 (m, 12 H) 0.90 (t, J
= 6.9 Hz, 3 H); ESI (m/z) 295 (M+H+) 317 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(2-hexylchroman-6-yl)-2-oxoethyl)
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25
malonate (8h)
8h was prepared using the same procedure as that described for compound 8a.
Yellow syrup(5.0g, 40.8%). 1H NMR (300 MHz, CDCl3): δ 7.72-7.70 (m, 2 H) 7.09 (s, 1 H) 6.81 (d, J = 9.0 Hz, 1
H) 4.29-4.22 (q, 4 H) 4.18 (s, 2 H) 4.13-4.04 (m, 1 H) 2.84-2.79 (m, 2 H) 2.00 (brs, 1
H) 1.96 (s, 3 H) 1.74-1.28 (m, 11 H) 1.24 (t, J = 6.9 Hz, 6 H) 0.89 (t, J = 6.9 Hz, 3 H);
ESI (m/z) 476 (M+H+) 498 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(2-hexylchroman-6-yl)ethyl)malonate (9h)
9h was prepared using the same procedure as that described for compound 9a.
Crude product as yellow oil(2.5g, 96.2% yield).
ESI (m/z) 462 (M+H+) 484 (M+Na
+)
Synthesis of N-(4-(2-hexylchroman-6-yl)-1-hydroxy-2-(hydroxymethyl)butan-2-yl)
acetamide (10h)
10h was prepared using the same procedure as that described for compound 10a.
White solid(1.2g, 36.6% yield).
mp: 46-49 oC;
1H NMR (300 MHz, CDCl3): δ 6.91 (s, 1 H) 6.84 (d, J = 8.1 Hz, 1 H)
6.68-6.55 (m, 1 H) 6.03-5.99 (m, 1 H) 3.92-3.60 (m, 4 H) 3.48 (s, 1 H) 2.79-2.43 (m,
5 H) 1.97 (s, 3 H) 2.04-1.27 (m, 13 H) 0.90 (t, J = 4.5 Hz, 3 H); ESI (m/z) 378 (M+H+)
400 (M+Na+)
Synthesis of 2-amino-2-(2-(2-hexylchroman-6-yl)ethyl)propane-1,3-diol (11h)
11h was prepared using the same procedure as that described for compound 11a.
White solid(0.4g, 54.1% yield).
mp: 56-59 oC;
1H NMR (300 MHz, CD3OD): δ 6.83 (s, 1 H) 6.76 (t, J = 7.2 Hz, 1 H)
6.57 (d, J = 7.8 Hz, 1 H) 6.45 (d, J = 8.1 Hz, 1 H) 3.62 (s, 1 H) 3.58 (s, 4 H) 2.78-2.19
(m, 5 H) 1.90-1.25 (m, 13 H) 0.86 (t, J = 6.6 Hz, 3 H); 13
C NMR (100MHz, CD3OD):
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δ ; HRMS calcd. for C20H34NO3 (M+H+) 336.2538, found 336.2536
Synthesis of benzyl (4-(2-hexylchroman-6-yl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)carbamate (12h)
12h was prepared using the same procedure as that described for compound 12a.
Colorless oil(150mg, 88.8% yield). 1H NMR (300 MHz, CDCl3): δ 7.36 (brs, 5 H) 6.89-6.83 (m, 2 H) 6.66-6.54 (m, 1 H)
5.09 (s, 2 H) 4.18-4.08 (m, 1 H) 3.90 (d, J = 11.7 Hz, 2 H) 3.67 (d, J = 11.4 Hz, 2 H)
2.54-1.23 (m, 18 H) 0.88 (t, J = 4.5 Hz, 3 H); ESI (m/z) 470 (M+H+)
Synthesis of benzyl ((2R)-1-((bis(benzyloxy)phosphoryl)oxy)-4-(2-hexylchroman
-6-yl)-2-(hydroxymethyl)butan-2-yl)carbamate (13h)
13h was prepared using the same procedure as that described for compound 13a.
Colorless oil(70mg, 30.0% yield). 1H NMR (300 MHz, CDCl3): δ 7.36-7.31 (m, 18 H) 5.17-5.00 (m, 6 H) 3.82-3.55 (m,
5 H) 2.60-1.28 (m, 18 H) 0.85 (t, J = 4.5 Hz, 3 H); ESI (m/z) 730 (M+H+)
Synthesis of 2-amino-4-(2-hexylchroman-6-yl)-2-(hydroxymethyl)butyl
dihydrogen phosphate (14h)
14h was prepared using the same procedure as that described for compound 14a.
White solid(30mg, 75.3% yield).
mp: 115-118 oC
;
1H NMR (300 MHz, CD3OD): δ 7.29-6.79 (m, 3 H) 3.96-3.61 (m, 5
H) 3.06-2.52 (m, 5 H) 1.89-1.24 (m, 13 H) 0.87 (t, J = 6.6 Hz, 3 H); 13
C NMR (100
MHz, CD3OD): δ 151.22, 142.25, 136.35, 129.49, 127.11, 121.14, 62.66, 62.02, 59.78,
53.97, 34.84, 32.40, 30.84, 29.46, 28.72, 27.36, 25.83, 24.72, 23.52, 14.46; HRMS
calcd. for C20H35NO6P (M+H+) 416.2197, found 416.2173
Synthesis of 1-(4-(4-butylphenoxy)phenyl)-2-chloroethanone (7i)
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7i was prepared using the same procedure as that described for compound 7a.
Yellow oil(14.2g, 95.9% yield). 1H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 8.7 Hz, 2 H) 7.21 (d, J = 8.1 Hz, 2 H) 6.99
(dd, J = 8.7 Hz, 2.7 Hz, 4 H) 4.65 (s, 2 H) 2.63 (t, J = 7.8 Hz, 2 H) 1.67-1.57 (m, 2 H)
1.42-1.34 (m, 2 H) 0.95 (t, J = 7.2 Hz, 3 H); ESI (m/z) 303 (M+H+) 325 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-butylphenoxy)phenyl)-2-oxoethyl)
malonate (8i)
8i was prepared using the same procedure as that described for compound 8a.
Yellow solid(6.9g, 30.4% yield).
mp: 160-163 oC;
1H NMR (300 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 2 H) 7.20 (d, J =
8.1 Hz, 2 H) 7.11 (brs, 1 H) 6.97 (d, J = 8.7 Hz, 4 H) 4.27 (dd, J = 14.1 Hz, 7.2 Hz, 4
H) 4.21 (s, 2 H) 2.65 (t, J = 7.8 Hz, 2 H) 1.97 (s, 3 H) 1.64-1.57 (m, 2 H) 1.41-1.29
(m, 2 H) 1.24 (t, J = 7.2 Hz, 6 H) 0.95 (t, J = 7.2 Hz, 3 H); ESI (m/z) 484 (M+H+) 506
(M+Na+)
Synthesis of diethyl 2-acetamido-2-(4-(4-butylphenoxy)phenethyl)malonate (9i)
9i was prepared using the same procedure as that described for compound 9a.
White solid(1.78g, 90.4% yield).
mp: 145-148 oC;
1H NMR (300MHz, CDCl3): δ 7.12 (t, J = 8.7 Hz, 4 H) 6.90 (dd, J =
8.1 Hz, 2.7 Hz, 4 H) 6.79 (brs, 1 H) 4.26-4.20 (m, 4 H) 2.69 (dd, J = 9.9 Hz, 7.2 Hz, 2
H) 2.59 (t, J = 7.5 Hz, 2 H) 2.46 (dd, J = 9.0 Hz, 6.6 Hz, 2 H) 2.02 (s, 3 H) 1.65-1.55
(m, 2 H) 1.41-1.33 (m, 2 H) 1.27 (t, J = 6.9 Hz, 6 H) 0.95 (t, J = 7.2 Hz, 3 H); ESI
(m/z) 470 (M+H+) 492 (M+Na
+)
Synthesis of N-(4-(4-(4-butylphenoxy)phenyl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)acetamide (10i)
10i was prepared using the same procedure as that described for compound 10a.
White solid(0.65g, 46.9% yield).
mp: 140-143 oC;
1H NMR (300 MHz, CDCl3): δ 7.13 (dd, J = 8.1 Hz, 5.7 Hz, 4 H)
6.90 (t, J = 7.8 Hz, 4 H) 5.92 (brs, 1 H) 3.86 (d, J = 11.7 Hz, 2 H) 3.79 (brs, 2 H) 3.63
(d, J = 11.1 Hz, 2 H) 2.65-2.55 (m, 4 H) 2.04-1.93 (m, 5 H) 1.63-1.53 (m, 2 H)
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1.42-1.29 (m, 2 H) 0.93 (t, J = 7.5 Hz, 3 H); ESI (m/z) 386 (M+H+)
Synthesis of 2-amino-2-(4-(4-butylphenoxy)phenethyl)propane-1,3-diol (11i)
11i was prepared using the same procedure as that described for compound 11a.
White solid(0.51g, 89.0% yield).
mp: 146-150 oC;
1H NMR (300 MHz, CD3OD): δ 7.17 (d, J = 8.4 Hz, 2 H) 7.11 (d, J
= 8.7 Hz, 2 H) 6.83 (dd, J = 8.4 Hz, 2.1 Hz, 4 H) 3.47 (q, J = 10.8 Hz, 4 H) 2.64-2.53
(m, 4 H) 1.66-1.51 (m, 4 H) 1.40-1.30 (m, 2 H) 0.92 (t, J = 7.2 Hz, 3 H); 13
C NMR
(100 MHz, CD3OD): δ 180.38, 157.04, 138.90, 130.58, 119.62, 119.54, 66.54, 56.75,
37.82, 35.86, 35.10, 29.68, 23.30, 14.26; HRMS calcd. for C21H30NO3 (M+H+)
344.2220, found 360.2223
Synthesis of benzyl (4-(4-(4-butylphenoxy)phenyl)-1-hydroxy-2-(hydroxymethyl)
butan-2-yl)carbamate (12i)
12i was prepared using the same procedure as that described for compound 12a.
Colorless oil(120mg, 96.7% yield). 1H NMR (300 MHz, CDCl3): δ 7.37 (brs, 5 H) 7.10 (t, J = 7.5 Hz, 4 H) 6.89 (d, J =
8.4 Hz, 4 H) 5.09 (s, 2 H) 3.92 (d, J = 12.0 Hz, 2 H) 3.68 (d, J = 11.1 Hz, 2 H) 2.58 (t,
J = 8.4 Hz, 4 H) 1.90 (t, J = 8.7 Hz, 2 H) 1.61-1.53 (m, 2 H) 1.39-1.32 (m, 2 H) 0.93
(t, J = 7.2 Hz, 3 H); ESI (m/z) 478 (M+H+)
Synthesis of benzyl (1-((bis(benzyloxy)phosphoryl)oxy)-4-(4-(4-butylphenoxy)
phenyl)-2-(hydroxymethyl)butan-2-yl)carbamate (13i)
13i was prepared using the same procedure as that described for compound 13a.
Colorless oil(70mg, 38.0% yield). 1H NMR (300 MHz, CDCl3): δ 7.32-7.24 (m, 15 H) 7.11 (d, J = 8.4 Hz, 2 H) 7.03 (d,
J = 8.1 Hz, 2 H) 6.88 (dd, J = 8.4 Hz, 4.8 Hz, 4 H) 5.09-4.96 (m, 6 H) 4.18-4.04 (m, 2
H) 3.60 (s, 2 H) 2.58 (t, J = 7.5 Hz, 2 H) 2.52-2.47 (m, 2 H) 2.11-2.07 (m, 1 H) 1.82-
1.76 (m, 1 H) 1.63-1.53 (m, 2 H) 1.39-1.29 (m, 2 H) 0.93 (t, J = 7.2 Hz, 3 H); ESI
(m/z) 738 (M+H+)
Synthesis of 2-amino-4-(4-(4-butylphenoxy)phenyl)-2-(hydroxymethyl)butyl
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dihydrogen phosphate (14i)
14i was prepared using the same procedure as that described for compound 14a.
White solid(25mg, 61.6% yield).
mp: 190-193 oC
;
1H NMR (300 MHz, CD3OD): δ 7.16 (d, J = 8.1 Hz, 2 H) 7.08 (d, J
= 8.1 Hz, 2 H) 6.80 (t, J = 6.9 Hz, 4 H) 3.96 (s, 2 H) 3.66 (s, 2 H) 2.63-2.50 (m, 4 H)
1.95-1.90 (m, 2 H) 1.58-1.48 (m, 2 H) 1.36-1.23 (m, 2 H) 0.88 (t, J = 7.2 Hz, 3 H) 13
C
NMR (100 MHz, CD3OD): δ 157.53, 156.69, 139.03, 137.01, 130.64, 119.70, 119.65,
65.82, 62.46, 61.36, 61.28, 35.86, 35.09, 34.91, 29.27, 23.30, 14.26; HRMS calcd. for
C21H31NO6P (M+H+) 424.1884, found 424.1869
Synthesis of 2-bromo-1-(4-phenoxyphenyl)ethanone (16, X=H):
Bromoacetyl bromide (23.7g, 115.0mmol) in CH2Cl2 (50mL) was added dropwise
to a cooled solution (0°C) of 15 (19.6g, 115.0mmol) in CH2Cl2 (150mL), then AlCl3
(16.1g, 121.0mmol) was added in portions in 30min. The solution was then allowed to
return to room temperature and stirred for further 2 h. The mixture was poured slowly
into 2NHCl-ice mixture (100mL) and stirred for 2 h. The aqueous phase was extracted
with CH2Cl2(20mL×3). The combined organic layers were washed with saturated aq.
NaHCO3 and brine, dried over Na2SO4, filtered and concentrated, yielding crude
product 16(X=H) (1.5g, 97.4% yield) as yellow oil.
ESI (m/z) 291 (M+H+); 313 (M+Na
+)
Synthesis of 2-bromo-1-(4-(4-bromophenoxy)phenyl)ethanone (16, X=Br):
16(X=Br) was prepared using the same procedure as that described for compound
16( X=H). Yellow oil(24.6g, 83.4% yield). 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J = 8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 6.98
(m, 4H), 4.40 (s, 2H); ESI (m/z) 371 (M+H+); 393 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-oxo-2-(4-phenoxyphenyl)ethyl)malonate
(17, X=H)
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17(X=H) was prepared using the same procedure as that described for compound
8a. Yellow oil(3.6g, 49.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.94 (d, J = 8.7 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.21
(t, J = 7.4 Hz, 1H), 7.12 (br, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H),
4.27 (q, J = 7.2 Hz, 4H), 4.22 (s, 2H), 1.98 (s, 3H), 1.25 (t, J = 7.2 Hz, 6H). ESI (m/z)
428 (M+H) +
;450 (M+Na+)
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-bromophenoxy)phenyl)-2-oxoethyl)
malonate (17, X=Br)
17(X=Br) was prepared using the same procedure as that described for compound
8a. Yellow oil(29.2g, 89.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.95 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 7.13
(br, 1H), 6.97 (m, 4H), 4.27 (m, 6H), 1.98 (s, 3H), 1.27 (m, 6H). ESI (m/z) 506 (M+H)
+
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-benzoylphenoxy)phenyl)-2-oxoethyl)
malonate (18a)
Benzoyl chloride (0.36 g, 2.58 mmol) in CH2Cl2(3mL) was added dropwise to a
cooled solution (0°C) of 17(X=H) (1.0 g, 2.34 mmol) in CH2Cl2(10mL), then AlCl3
(1.56 g, 11.7 mmol) was added in portions in 30min. The solution was then allowed to
return to room temperature and stirred for further 4 h. The mixture was poured slowly
into 2NHCl-ice mixture(10mL) and stirred for 2 h. The aqueous phase was extracted
with CH2Cl2(3mL×3). The combined organic layers were washed with saturated aq.
NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was
purified by silica gel flash column chromatography (EtOAc/PE) to afford compound
18a(0.65g, 52.0% yield) as brown oil. 1H NMR (300 MHz, CDCl3) δ: 8.00 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.80
(d, J = 8.4 Hz, 2H), 7.59 (m, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.09 (m, 4H), 4.26 (m, 6H),
1.98 (s, 3H), 1.28 (m, 6H). ESI (m/z) 532 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-(4-methylbenzoyl)phenoxy)
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phenyl)-2-oxoethyl)malonate (18b)
18b was prepared using the same procedure as that described for compound 18a.
Yellow oil(0.55g, 55.0% yield) 1H NMR (300 MHz, CDCl3) δ: 8.00 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.72
(d, J = 8.1 Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 7.10 (m, 4H), 4.28 (m, 6H), 2.45 (s, 3H),
1.99 (s, 3H), 1.25 (t, J = 7.1 Hz, 6H). ESI (m/z) 546 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-(4-ethylbenzoyl)phenoxy)phenyl)
-2-oxoethyl)malonate (18c)
18c was prepared using the same procedure as that described for compound 18a.
Yellow solid(0.51g, 39.0% yield)
mp:72-74 oC;
1H NMR (300 MHz, CDCl3) δ: 8.01 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 8.4
Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.11 (m, 4H), 4.28 (m,
6H), 2.74 (q, J = 7.7 Hz, 2H), 1.99 (s, 3H), 1.28 (m, 9H). ESI (m/z) 560 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-(4-fluorobenzoyl)phenoxy)phenyl)
-2-oxoethyl)malonate (18d)
18d was prepared using the same procedure as that described for compound 18a.
Yellow oil(0.68g, 53.0% yield) 1H NMR (300 MHz, CDCl3) δ: 8.01 (d, J = 9.0 Hz, 2H), 7.84 (m, 4H), 7.12 (m, 6H),
4.27 (m, 6H), 1.99 (s, 3H), 1.25 (t, J = 7.2 Hz, 6H). ESI (m/z) 550 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-(4-chlorobenzoyl)phenoxy)phenyl)-2-
oxoethyl)malonate (18e)
18e was prepared using the same procedure as that described for compound 18a.
Yellow oil(0.7g, 53.0% yield) 1H NMR (300 MHz, CDCl3) δ: 8.00 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.75
(d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.10 (m, 4H), 4.27 (m, 6H), 1.98 (s, 3H),
1.25 (t, J = 7.1 Hz, 6H). ESI (m/z) 566 (M+H) +
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Synthesis of diethyl 2-acetamido-2-(4-(4-benzylphenoxy)phenethyl)malonate
(19a)
A solution of 18a (1.6 g, 3.0 mmol) in CH2Cl2 (20mL) was added dropwise to a
solution of Et3SiH (2.5g, 21.1 mmol) in CH2Cl2 at room temperature under Ar2
protection. TiCl4 (4.0g, 21.1 mmol) was added with a syringe and the reaction mixture
was stirred for 12 h at room temperature. The solution was poured slowly into ice
water (20mL). The aqueous phase was extracted with CH2Cl2(5mL×3). The combined
organic layers were washed with brine, dried over Na2SO4, filtered and concentrated.
The residue was purified by silica gel flash column chromatography (EtOAc/PE) to
afford compound 19a (1.0g, 67.0% yield) as white solid.
mp: 62-64 oC;
1H NMR (300 MHz, CDCl3) δ: 7.28 (m, 2H), 7.20 (m, 3H), 7.11 (m,
4H), 6.89 (m, 4H), 6.79 (br, 1H), 4.24 (m, 4H), 3.95 (s, 2H), 2.68 (m, 2H), 2.46 (m,
2H), 2.01 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). ESI (m/z) 504 (M+H) +
Synthesis of diethyl 2-acetamido-2-(4-(4-(4-methylbenzyl)phenoxy)phenethyl)
malonate (19b)
19b was prepared using the same procedure as that described for compound 19a.
White solid(0.43g, 83.0% yield)
mp: 20-22 oC;
1H NMR (300 MHz, CDCl3) δ: 7.09 (m, 8H), 6.88 (m, 4H), 6.77 (br,
1H), 4.22 (q, J = 7.2 Hz, 4H), 3.91 (s, 2H), 2.67 (m, 2H), 2.45 (m, 2H), 2.32 (s, 3H),
2.01 (s, 3H), 1.25 (t, J = 7.2 Hz, 6H). ESI (m/z)518(M+H) +
Synthesis of diethyl 2-acetamido-2-(4-(4-(4-ethylbenzyl)phenoxy)phenethyl)
malonate (19c)
19c was prepared using the same procedure as that described for compound 19a.
Colorless oil(0.4g, 84.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.11 (m, 8H), 6.89 (m, 4H), 6.79 (br, 1H), 4.23 (m,
4H), 3.92 (s, 2H), 2.64 (m, 4H), 2.46 (m, 2H), 2.02 (s, 3H), 1.24 (m, 9H). ESI (m/z)
532 (M+H) +
Synthesis of diethyl 2-acetamido-2-(4-(4-(4-fluorobenzyl)phenoxy)phenethyl)
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malonate (19d)
19d was prepared using the same procedure as that described for compound 19a.
White solid(0.47g, 72.0% yield)
mp: 32-34 oC;
1H NMR (300 MHz, CDCl3) δ: 7.11 (m, 6H), 6.97 (t, J = 8.7 Hz, 2H),
6.89 (m, 4H), 6.78 (br, 1H), 4.23 (m, 4H), 3.92 (s, 2H), 2.68 (m, 2H), 2.46 (m, 2H),
2.01 (s, 3H), 1.25 (t, J = 7.1 Hz, 6H). ESI (m/z) 522 (M+H) +
Synthesis of diethyl 2-acetamido-2-(4-(4-(4-chlorobenzyl)phenoxy)phenethyl)
malonate (19e)
19e was prepared using the same procedure as that described for compound 19a.
Yellow oil(0.6g, 91.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.25 (m, 2H), 7.11 (m, 6H), 6.89 (m, 4H), 6.80 (br,
1H), 4.21 (q, J = 7.1 Hz, 4H), 3.91 (s, 2H), 2.68 (m, 2H), 2.46 (m, 2H), 2.02 (s, 3H),
1.26 (t, J = 7.1 Hz, 6H). ESI (m/z) 538 (M+H) +
Synthesis of 2-amino-2-(4-(4-benzylphenoxy)phenethyl)propane-1,3-diol (20a)
20a was prepared using the same procedure as that described for compound 11a.
White solid (0.6g, two steps 70.6% yield)
m.p.: 205-208 °C. 1H NMR (300 MHz, CD3OD) δ: 7.17 (m, 9H), 6.83 (m, 4H), 3.88
(s, 2H), 3.65 (s, 4H), 2.61 (m, 2H), 1.90 (m, 2H); 13
C NMR (400MHz, CD3OD) δ:
157.3, 157.1, 142.8, 137.7, 137.3, 131.2, 130.6, 129.8, 129.5, 127.1, 119.8, 119.7,
62.5, 62.0, 42.0, 34.8, 29.3. HRMS calcd for C24H28NO3 (M+H+) 378.2064; found:
378.2057.
Synthesis of 2-amino-2-(4-(4-(4-methylbenzyl)phenoxy)phenethyl)propane-1,3-
diol (20b)
20b was prepared using the same procedure as that described for compound 11a.
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White solid (0.3g, two steps 84.6% yield)
m.p.: 218-220 °C. 1H NMR (300 MHz, CD3OD) δ: 7.14 (d, J = 8.7 Hz, 2H), 7.08 (d, J
= 8.4 Hz, 2H), 7.01 (m, 4H), 6.81 (m, 4H), 3.83 (s, 2H), 3.63 (s, 4H), 2.57 (m, 2H),
2.23 (s, 3H), 1.88 (m, 2H); 13
C NMR (400 MHz, CD3OD) δ: 157.4, 157.0, 139.7,
138.1, 137.2, 136.6, 131.1, 130.6, 130.1, 129.7, 119.8, 119.7, 62.5, 62.0, 41.6, 34.8,
29.3, 21.0. HRMS calcd for C25H30NO3(M+H+) 392.2220; found: 392.2229.
Synthesis of 2-amino-2-(4-(4-(4-ethylbenzyl)phenoxy)phenethyl)propane-1,3-diol
(20c)
20c was prepared using the same procedure as that described for compound 11a.
White solid (0.18g, two steps 59.3% yield)
m.p.: 176-178 °C. 1H NMR (300 MHz, CD3OD) δ: 7.14 (d, J = 8.4 Hz, 2H), 7.08 (d, J
= 8.1 Hz, 2H), 7.03 (m, 4H), 6.81 (m, 4H), 3.83 (s, 2H), 3.63 (s, 4H), 2.56 (m, 4H),
1.88 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H); 13
C NMR (400 MHz, CD3OD) δ: 157.4, 157.0,
143.2, 139.9, 138.1, 137.2, 131.1, 130.6, 129.8, 128.9, 119.8, 119.7, 62.5, 62.0, 41.6,
34.8, 29.4, 29.3, 16.3. HRMS calcd for C26H32NO3 (M+H+) 406.2377; found:
406.2383.
Synthesis of 2-amino-2-(4-(4-(4-fluorobenzyl)phenoxy)phenethyl)propane-1,3-
diol (20d)
20d was prepared using the same procedure as that described for compound 11a.
White solid (0.3g, two steps 86.5% yield)
m.p.: 178-180 °C. 1H NMR (300 MHz, CD3OD) δ: 7.12 (m, 6H), 6.93 (m, 2H), 6.82
(m, 4H), 3.87 (s, 2H), 3.63 (s, 4H), 2.59 (m, 2H), 1.89 (m, 2H); 13
C NMR (500 MHz,
CD3OD) δ: 162.8 (J = 241 Hz), 157.3, 157.2, 138.8 (J = 3 Hz), 137.6, 137.3, 131.4 (J
= 8 Hz), 131.1, 130.6, 119.9, 119.8, 116.0 (J = 21 Hz), 62.5, 62.0, 41.1, 34.8, 29.4.
HRMS calcd for C24H27FNO3(M+H+)396.1969; found: 396.1987.
Synthesis of 2-amino-2-(4-(4-(4-chlorobenzyl)phenoxy)phenethyl)propane-1,3-
diol (20e)
20e was prepared using the same procedure as that described for compound 11a.
White solid (0.37g, two steps 83.3% yield)
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m.p.: 172-175 °C. 1H NMR (300 MHz, CD3OD) δ: 7.19 (m, 3H), 7.11 (m, 5H), 6.83
(m, 4H), 3.86 (s, 2H), 3.63 (s, 4H), 2.59 (m, 2H), 1.89 (m, 2H). 13
C NMR (500 MHz,
CD3OD) δ: 157.3, 157.2, 141.7, 137.3, 137.2, 132.9, 131.4, 131.2, 130.6, 129.5, 119.9,
119.8, 62.5, 62.0, 41.2, 34.8, 29.4. HRMS calcd for C24H27ClNO3(M+H+) 412.1674;
found: 412.1688.
Synthesis of 2-amino-4-(4-(4-benzylphenoxy)phenyl)-2-(hydroxymethyl)butyl
dihydrogen phosphate (21a)
21a was prepared using the same procedure as that described for compound 14a.
White solid (15mg, three steps 13.9% yield)
m.p.: 195-198 °C. 1H NMR (300 MHz, CD3OD) δ: 7.15 (m, 9H), 6.81 (m, 4H), 3.94
(m, 2H), 3.88 (s, 2H), 3.64 (m, 2H), 2.61 (m, 2H), 1.89 (m, 2h). 13
C NMR (600 MHz,
CD3OD) δ: 157.3, 157.1, 142.8, 137.8, 137.2, 131.2, 130.7, 129.8, 129.5, 127.1, 119.8,
119.7, 65.8, 62.5, 61.4, 42.0, 34.9, 29.3. HRMS calcd for C24H29NO6P(M+H+)
458.1727; found: 458.1727.
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4-(4-(4-methylbenzyl)phenoxy)
phenyl)butyl dihydrogen phosphate (21b)
21b was prepared using the same procedure as that described for compound 14a.
White solid (15mg, three steps 13.4% yield)
m.p.: 190-192 °C. 1H NMR (300 MHz, CD3OD) δ: 7.13 (d, J = 8.1 Hz, 2H), 7.06 (d, J
= 8.1 Hz, 2H), 6.99 (m, 4H), 6.79 (m, 4H), 3.91 (m, 2H), 3.80 (s, 2H), 3.62 (m, 2H),
2.57 (m, 2H), 2.20 (s, 3H), 1.89 (m, 2H). 13
C NMR (500 MHz, DMSO) δ: 155.3,
155.2, 138.5, 136.8, 136.7, 135.1, 130.3, 129.9, 129.3, 128.8, 118.8, 118.5, 64.3, 61.2,
59.5, 33.8, 27.8, 20.8. HRMS calcd for C25H31NO6P(M+H+) 472.1884; found:
472.1860.
Synthesis of 2-amino-4-(4-(4-(4-ethylbenzyl)phenoxy)phenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (21c)
21c was prepared using the same procedure as that described for compound 14a.
White solid (10mg, three steps 9.1% yield)
m.p.: 198-200 °C. 1H NMR (300 MHz, CD3OD) δ: 7.16 (d, J = 8.1 Hz, 2H), 7.09 (d, J
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= 8.1 Hz, 2H), 7.04 (m, 4H), 6.81 (m, 4H), 3.94 (m, 2H), 3.84 (s, 2H), 3.65 (m, 2H),
2.56 (m, 4H), 1.92 (m, 2H), 1.14 (t, J = 7.7 Hz, 3H). 13
C NMR (500 MHz, CD3OD) δ:
157.7, 157.3, 143.5, 140.3, 138.3, 137.4, 131.4, 131.0, 130.1, 129.2, 120.1, 120.0,
66.0, 62.8, 61.6, 41.9, 35.2, 29.8, 29.6, 16.6. HRMS calcd for C26H33NO6P (M+H+)
486.2040; found: 486.2019.
Synthesis of 2-amino-4-(4-(4-(4-fluorobenzyl)phenoxy)phenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (21d)
21d was prepared using the same procedure as that described for compound 14a.
White solid (20mg, three steps 16.5% yield)
m.p.: 203-205 °C. 1H NMR (300 MHz, CD3OD) δ: 7.13 (m, 6H), 6.93 (t, J = 8.8 Hz,
2H), 6.82 (m, 4H), 3.94 (m, 2H), 3.86 (m, 2H), 3.65 (m, 2H), 2.61 (m, 2H), 1.91 (m,
2H). 13
C NMR (500 MHz, DMSO) δ: 160.8 (J = 240 Hz), 155.3, 154.9, 137.6, 136.8,
136.1, 130.5 (J = 8 Hz), 130.2, 129.8, 118.7, 118.5, 115.2 (J = 21 Hz), 64.3, 61.0, 59.3,
33.7, 27.7. HRMS calcd for C24H28FNO6P (M+H+) 476.1633; found: 476.1610.
Synthesis of 2-amino-4-(4-(4-(4-chlorobenzyl)phenoxy)phenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (21e)
21e was prepared using the same procedure as that described for compound 14a.
White solid (15mg, three steps 12.7% yield)
m.p.: 215-217 °C. 1H NMR (400 MHz, CD3OD) δ: 7.17 (m, 4H), 7.09 (m, 4H), 6.80
(m, 4H), 3.92 (m, 2H), 3.85 (m, 2H), 3.64 (m, 2H), 2.60 (m, 2H), 1.90 (m, 2H). 13
C
NMR (500 MHz, CD3OD) δ: 157.4, 157.1, 141.7, 137.7, 137.1, 132.9, 131.4, 131.2,
130.7, 129.5, 119.9, 119.7, 66.1, 63.1, 60.7, 41.2, 35.4, 29.4. HRMS calcd for
C24H28ClNO6P (M+H+) 492.1337; found: 492.1324.
Synthesis of diethyl 2-acetamido-2-(4-phenoxyphenethyl)malonate (22, X=H)
22(X=H) was prepared using the same procedure as that described for compound
9a. Crude product as yellow oil (10.0g, 98.9% yield)
ESI (m/z) 414 (M+H) +
; 436(M+Na)+
Synthesis of diethyl 2-acetamido-2-(4-(4-bromophenoxy)phenethyl)malonate (22,
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X=Br)
22(X=Br) was prepared using the same procedure as that described for compound
9a. White solid (1.1g, 98.0% yield)
mp: 53-54 oC;
1H NMR (300 MHz, CDCl3) δ: 7.40 (d, J = 8.7 Hz, 2H), 7.12 (d, J =
8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.85 (m, 3H), 4.22 (q, J = 7.2 Hz, 4H), 2.68 (m,
2H), 2.47 (m, 2H), 2.03 (s, 3H), 1.26 (t, J = 7.2 Hz, 6H). ESI (m/z) 492 (M+H) +
Synthesis of diethyl 2-(4-([1,1'-biphenyl]-4-yloxy)phenethyl)-2-acetamido
malonate (23a)
To a solution of 22(X=Br)(0.4g,0.8mmol) in a mixture of toluene and
EtOH(6mL/2mL) was added phenylboronic acid(0.1g, 0.8 mmol), Pd(PPh)4(0.04,
0.03mmol) and 2M aq.Na2CO3(3mL). The mixture was heated to reflux for 3h under
Ar2 proteciton, then cooled to room tempeture. The aqueous phase was extracted with
EtOAc(3mL×3). The combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column
chromatography (EtOAc/PE) to afford compound 23a (0.25g, 63.0% yield) as white
solid.
mp: 62-64 oC;
1H NMR (300 MHz, CDCl3) δ: 7.55 (m, 4H), 7.43 (t, J =7.5 Hz, 2H),
7.32 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.97 (d, J =
8.4 Hz, 2H), 6.79 (br, 1H), 4.22 (q, J = 6.9 Hz, 4H), 2.70 (m, 2H), 2.47 (m, 2H), 2.02
(s, 3H), 1.26 (t, J = 6.9 Hz, 6H). ESI (m/z) 490 (M+H) +
Synthesis of diethyl 2-acetamido-2-(4-((4'-ethyl-[1,1'-biphenyl]-4-yl)oxy)
phenethyl)malonate (23b)
23b was prepared using the same procedure as that described for compound 23a.
Yellow solid (0.3g, 71.0% yield)
mp: 116-118 oC;
1H NMR (300 MHz, CDCl3) δ: 7.50 (m, 4H), 7.27 (m, 2H), 7.13 (d,
J = 8.1 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.80 (br, 1H), 4.22
(q, J = 6.6 Hz, 4H), 2.69 (m, 4H), 2.47 (m, 2H), 2.03 (s, 3H), 1.27 (m, 9H). ESI (m/z)
518 (M+H) +
Synthesis of diethyl 2-acetamido-2-(4-((3'-methoxy-[1,1'-biphenyl]-4-yl)oxy)
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phenethyl)malonate (23c)
23c was prepared using the same procedure as that described for compound 23a.
Yellow oil (0.62g, 98.0% yield) 1H NMR (600 MHz, CDCl3) δ: 7.52 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.14
(m, 3H), 7.09 (t, J = 2.1 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H),
6.88 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.80 (br, 1H), 4.26 (m, 4H), 3.90 (s, 3H), 2.74
(m, 2H), 2.53 (m, 2H), 2.08 (s, 3H), 1.33 (t, J = 6.9 Hz, 6H). ESI (m/z) 520 (M+H) +
Synthesis of 2-(4-([1,1'-biphenyl]-4-yloxy)phenethyl)-2-aminopropane-1,3-diol
(24a)
24a was prepared using the same procedure as that described for compound 11a.
White solid (0.44g, two steps 85.5% yield)
m.p.: 180-182 °C. 1H NMR (300 MHz, CD3OD) δ: 7.53 (m, 4H), 7.36 (t, J = 7.5 Hz,
2H), 7.26 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.92
(d, J = 8.4 Hz, 2H), 3.65 (s, 4H), 2.62 (m, 2H), 1.92 (m, 2H). 13
C NMR (400 MHz,
CD3OD) δ: 158.5, 157.0, 141.8, 137.7, 137.6, 130.7, 129.9, 129.4, 128.1, 127.7, 120.2,
119.8, 62.5, 62.0, 34.8, 29.4. HRMS calcd for C23H26NO3(M+H+) 364.1907; found:
364.1918.
Synthesis of 2-amino-2-(4-((4'-ethyl-[1,1'-biphenyl]-4-yl)oxy)phenethyl)propane-
1,3-diol (24b)
24b was prepared using the same procedure as that described for compound 11a.
White solid (0.13g, two steps 58.8% yield)
m.p.: 238-240 °C. 1H NMR (300 MHz, CD3OD) δ: 7.52(d, J =8.7 Hz, 2H), 7.44 (d, J
= 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 4H), 6.93 (m, 4H), 3.65 (s, 4H), 2.62 (m, 4H), 1.92
(m, 2H), 1.20 (t, J = 7.5 Hz, 3H). 13
C NMR (400 MHz, CD3OD) δ: 158.3, 157.1,
144.5, 139.1, 137.6, 137.5, 130.7, 129.3, 129.2, 127.7, 120.2, 119.8, 62.5, 62.0, 34.8,
29.5, 29.4, 16.2. HRMS calcd for C25H30NO3 (M+H+) 392.2220; found: 392.2203.
Synthesis of 2-amino-2-(4-((3'-methoxy-[1,1'-biphenyl]-4-yl)oxy)phenethyl)
propane-1,3-diol (24c)
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39
24c was prepared using the same procedure as that described for compound 11a.
White solid (0.3g, two steps 68.0% yield)
m.p.: 210-212 °C. 1H NMR (600 MHz, CD3OD) δ: 7.47 (d, J = 7.8 Hz, 2H), 7.22 (t, J
= 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.2 Hz, 1H), 7.01 (m, 1H), 6.92
(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.79 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H),
3.77 (s, 3H), 3.64 (s, 4H), 2.63 (m, 2H), 1.93 (m, 2H). 13
C NMR (600 MHz, CD3OD)
δ: 161.6, 158.6, 156.9, 143.2, 137.7, 137.4, 130.9, 130.7, 129.4, 120.3, 120.2, 119.7,
113.5, 113.4, 62.5, 62.1, 55.7, 34.8, 29.4. HRMS calcd for C24H28NO4 (M+H+)
394.2013; found: 394.1996.
Synthesis of 4-(4-([1,1'-biphenyl]-4-yloxy)phenyl)-2-amino-2-(hydroxymethyl)
butyldihydrogen phosphate (25a)
25a was prepared using the same procedure as that described for compound 14a.
White solid (10mg, three steps 8.3% yield)
m.p.: 115-118 °C. 1H NMR (300 MHz, CD3OD) δ: 7.53 (m, 4H), 7.33 (m, 3H), 7.25
(m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.11 (m, 2H), 3.67 (m, 2H),
2.54 (m, 2H), 1.95 (m, 2H). 13
C NMR (400 MHz, CD3OD) δ: 158.8, 156.4, 141.9,
139.1, 137.3, 130.9, 129.8, 129.3, 129.0, 127.7, 120.2, 119.6, 67.0, 62.8, 60.2, 34.0,
29.6. HRMS calcd for C23H27NO6P(M+H+) 444.1571; found: 444.1555.
Synthesis of 2-amino-4-(4-((4'-ethyl-[1,1'-biphenyl]-4-yl)oxy)phenyl)-2-
(hydroxymethyl)butyl dihydrogen phosphate (25b)
25b was prepared using the same procedure as that described for compound 14a.
White solid (15mg, three steps 14.2% yield)
m.p.: 190-192 °C. 1H NMR (300 MHz, CD3OD) δ: 7.51 (d, J = 8.4 Hz, 2H), 7.44 (d, J
= 8.1Hz, 2H), 7.19 (m, 4H), 6.92 (m, 4H), 3.94 (m, 2H), 3.66 (m, 2H), 2.61 (m, 4H),
1.95 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). 13
C NMR (500 MHz, CD3OD) δ: 158.6, 157.4,
144.7, 139.5, 137.8, 131.1, 129.6, 129.4, 128.0, 120.5, 120.1, 62.8, 61.6, 58.6, 35.2,
29.8, 18.7, 16.5. HRMS calcd for C25H31NO6P(M+H+) 472.1884; found: 472.1872.
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4-((3'-methoxy-[1,1'-biphenyl]-4-yl)
oxy)phenyl)butyl dihydrogen phosphate (25c)
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25c was prepared using the same procedure as that described for compound 14a.
White solid (35mg, three steps 24.4% yield)
m.p.: 216-218 °C. 1H NMR (400 MHz, CD3OD) δ: 7.52 (d, J = 8.4 Hz, 2H), 7.26 (t, J
= 8.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.95 (d,
J = 8.4 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 3.95 (m, 2H), 3.78
(s, 3H), 3.66 (m, 2H), 2.64 (m, 2H), 1.95 (m, 2H). 13
C NMR (600 MHz, CD3OD) δ:
162.4, 159.5, 157.7, 144.1, 138.4, 138.2, 131.6, 130.2, 121.1, 121.0, 120.5, 114.3,
114.2, 66.6, 63,3, 62.2, 56.5, 35.7, 30.1. HRMS calcd for C24H29NO7P(M+H+)
474.1676; found: 474.1662.
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-chloroacetyl)phenoxy)phenethyl)
malonate (26)
Chloroacetyl chloride (4.7 g, 41.2 mmol l) in CH2Cl2(20mL) was added dropwise to
a cooled solution (0°C) of 22(X=H) (15.5 g, 37.5 mmol) in CH2Cl2(150mL), then
AlCl3 (25 g, 188 mmol) was added in portions in 30min. The solution was then
allowed to return to room temperature and stirred for further 5 h. The mixture was
poured slowly into 2NHCl-ice mixture (50mL) and stirred for 2h. The aqueous phase
was extracted with CH2Cl2 (10mL×3). The combined organic layers were washed with
saturated aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The
residue was purified by silica gel flash column chromatography (EtOAc/PE) to afford
compound 26 (4.1g, 22.4% yield) as yellow solid.
mp: 78-80 oC;
1H NMR (300 MHz, CDCl3): δ 7.93 (d, J = 8.7 Hz, 2 H) 7.19 (d, J =
8.7 Hz, 2 H) 6.98 (d, J = 8.7 Hz, 4 H) 6.81 (brs, 1 H) 4.65 (s, 2 H) 4.28-4.20 (m, 4 H)
2.70 (dd, J = 11.4 Hz, 7.2 Hz, 2 H) 2.50 (dd, J = 9.3 Hz, 5.1 Hz, 2 H) 2.04 (s, 3 H)
1.25 (t, J = 7.2 Hz, 6 H); ESI (m/z) 490 (M+H+) 512 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-acetoxyacetyl)phenoxy)phenethyl)
malonate (27a)
To a solution of 26 (1.7 g, 3.4 mmol) in CH3CN (20mL) was added acetic acid(0.47
g, 7.8 mmol) and Et3N(0.72 g, 7.2 mmol). The mixture was heated to reflux for 2h,
then concentrated. The residue was diluted with CH2Cl2 (30mL), washed with brine,
dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel
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flash column chromatography (EtOAc/PE) to afford compound 27a (1.6g, 92.8%
yield) as yellow syrup. 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 8.7 Hz, 2 H) 7.18 (d, J = 8.7 Hz, 2 H) 6.98
(d, J = 8.7 Hz, 4 H) 6.80 (brs, 1 H) 5.30 (d, J = 1.5 Hz, 2 H) 4.28-4.20 (m, 4 H) 2.70
(dd, J = 11.4 Hz, 7.5 Hz, 2 H) 2.50 (dd, J = 9.6 Hz, 5.7 Hz, 2 H) 2.23 (s, 3 H) 2.03 (s,
3 H) 1.27 (t, J = 7.2 Hz, 6 H); ESI (m/z) 514 (M+H+) 536 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-(propionyloxy)acetyl)phenoxy)
phenethyl)malonate (27b)
27b was prepared using the same procedure as that described for compound 27a.
Yellow solid (1.1g, 86.9% yield)
mp: 84-86 oC;
1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 8.7 Hz, 2 H) 7.18 (d, J =
8.7 Hz, 2 H) 6.98 (d, J = 8.7 Hz, 4 H) 6.80 (brs, 1 H) 5.30 (s, 2 H) 4.27-4.20 (m, 4 H)
2.70 (dd, J = 10.8 Hz, 6.9 Hz, 2 H) 2.56-2.46 (m, 4 H) 2.03 (s, 3 H) 1.29-1.19 (m, 9
H); ESI (m/z) 528 (M+H+) 550 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-((cyclopropanecarbonyl)oxy)acetyl)
phenoxy)phenethyl)malonate (27c)
27c was prepared using the same procedure as that described for compound 27a.
Yellow syrup (1.2g, 82.5% yield) 1H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 6.9 Hz, 2 H) 7.17 (d, J = 7.2 Hz, 2 H) 6.97
(d, J = 7.2 Hz, 4 H) 6.79 (brs, 1 H) 5.29 (s, 2 H) 4.23 (q, J = 7.2 Hz, 4 H) 2.70 (dd, J =
8.7 Hz, 7.2 Hz, 2 H) 2.50 (dd, J = 8.1 Hz, 6.9 Hz, 2 H) 2.02 (s, 3 H) 1.79-1.78 (m, 1 H)
1.26 (t, J = 7.2 Hz, 6 H) 1.03 (m, 2 H) 0.96 (m, 2 H); ESI (m/z) 540(M+H+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-methyloxazol-4-yl)phenoxy)phenethyl)
malonate (28a)
To a solution of 27a (1.62 g, 3.2 mmol) in xylene(30mL) was added acetamide
(0.93 g, 15.8 mmol) and 47%BF3·Et2O(0.3 mL). The mixture was heated to reflux for
40h, then concentrated. The residue was diluted with EtOAc(40mL), washed with
brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica
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gel flash column chromatography (EtOAc/PE) to afford compound 28a (1.2g, 75.2%
yield) as yellow solid.
mp: 112-114 oC;
1H NMR (300 MHz, CDCl3): δ 7.75 (s, 1 H) 7.65 (d, J = 9.0 Hz, 2 H)
7.12 (d, J = 8.4 Hz, 2 H) 6.99 (d, J = 8.4 Hz, 2 H) 6.94 (d, J = 8.4 Hz, 2 H) 6.78 (brs,
1 H) 4.27-4.17 (m, 4 H) 2.69 (dd, J = 11.1 Hz, 6.9 Hz, 2 H) 2.51-2.44 (m, 5 H) 2.02 (s,
3 H) 1.26 (t, J = 7.2 Hz, 6 H); ESI (m/z) 495 (M+H+) 517 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-ethyloxazol-4-yl)phenoxy)phenethyl)
malonate (28b)
28b was prepared using the same procedure as that described for compound 28a.
Yellow oil (0.85g, 79.7% yield) 1H NMR (300 MHz, CDCl3): δ 7.76 (s, 1 H) 7.66 (d, J = 8.4 Hz, 2 H) 7.12 (d, J = 8.4
Hz, 2 H) 6.99 (d, J = 8.7 Hz, 2 H) 6.93 (d, J = 8.7 Hz, 2 H) 6.79 (brs, 1 H) 4.25-4.18
(m, 4 H) 2.84 (q, J = 7.8 Hz, 2 H) 2.69 (dd, J = 11.1 Hz, 7.2 Hz, 2 H) 2.48 (dd, J =
14.1 Hz, 5.4 Hz, 2 H) 2.02 (s, 3 H) 1.37 (t, J = 7.5 Hz, 3 H) 1.26 (t, J = 7.2 Hz, 6 H);
ESI (m/z) 509 (M+H+) 531 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-cyclopropyloxazol-4-yl)phenoxy)
phenethyl)malonate (28c)
28c was prepared using the same procedure as that described for compound 28a.
Yellow oil (0.4g, 34.9% yield) 1H NMR (300 MHz, CDCl3): δ 7.68 (s, 1 H) 7.66 (d, J = 8.4 Hz, 2 H) 7.11 (d, J = 8.1
Hz, 2 H) 6.99 (d, J = 8.7 Hz, 2 H) 6.93 (d, J = 8.7 Hz, 2 H) 6.79 (brs, 1 H) 4.29-4.19
(m, 4 H) 2.69 (dd, J = 10.5 Hz, 6.3 Hz, 2 H) 2.45 (dd, J = 8.7 Hz, 5.1 Hz, 2 H)
2.23-2.17 (m, 1 H) 2.02 (s, 3 H) 1.27 (t, J = 7.2 Hz, 6 H) 1.23-0.99 (m, 4 H); ESI (m/z)
521(M+H+)
Synthesis of 2-amino-2-(4-(4-(2-methyloxazol-4-yl)phenoxy)phenethyl)propane-
1,3-diol (29a)
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29a was prepared using the same procedure as that described for compound 11a.
White solid (0.27g, two steps 58.2% yield)
mp: 179-181 oC;
1H NMR (300 MHz, CD3OD): δ 8.03 (s, 1 H) 7.63 (d, J = 8.7 Hz, 2
H) 7.22 (d, J = 8.1 Hz, 2 H) 6.92 (d, J = 8.1 Hz, 2 H) 6.91 (d, J = 8.1 Hz, 2 H) 3.65 (s,
4 H) 2.66-2.60 (m, 2 H) 2.44 (s, 3 H) 1.95-1.89 (m, 2 H); 13
C NMR (100 MHz,
CD3OD): δ 163.95, 158.99, 156.64, 141.20, 137.93, 134.96, 130.79, 128.00, 127.18,
120.39, 119.58, 62.51, 62.06, 34.76, 29.39, 13.55; HRMS calcd. for C21H25N2O4
(M+H+) 369.1808, found 369.1814
Synthesis of 2-amino-2-(4-(4-(2-ethyloxazol-4-yl)phenoxy)phenethyl)propane-
1,3-diol (29b)
29b was prepared using the same procedure as that described for compound 11a.
White solid (0.4g, two steps 62.1% yield)
mp: 166-169 oC;
1H NMR (300 MHz, CD3OD): δ 8.37 (s, 1 H) 7.68 (d, J = 8.4 Hz, 2
H) 7.27 (d, J = 8.1 Hz, 2 H) 7.02 (d, J = 8.4 Hz, 2 H) 6.96 (d, J = 7.8 Hz, 2 H) 3.68 (s,
4 H) 3.04 (q, 2 H) 2.69-2.64 (m, 2 H) 1.98-1.92 (m, 2 H) 1.41 (t, J = 7.8 Hz, 3 H); 13
C
NMR (100 MHz, CD3OD): δ 169.75, 160.19, 156.05, 138.41, 137.97, 136.47, 130.93,
128.69, 123.33, 120.76, 119.54, 62.50, 62.03, 34.71, 29.41, 22.26, 10.65; HRMS
calcd. for C22H27N2O4 (M+H+) 383.1965, found 383.1971
Synthesis of 2-amino-2-(4-(4-(2-cyclopropyloxazol-4-yl)phenoxy)phenethyl)
propane-1,3-diol (29c)
29c was prepared using the same procedure as that described for compound 11a.
White solid (74mg, two steps 34.2% yield)
mp: 65-68 oC;
1H NMR(300 MHz, CD3OD): δ 8.19 (s, 1 H) 7.58 (d, J = 8.4 Hz, 2 H)
7.19 (d, J = 8.4 Hz, 2 H) 6.92 (d, J = 8.7 Hz, 2 H) 6.87 (d, J = 8.7 Hz, 2 H) 3.60 (s, 4
H) 2.62-2.56 (m, 2 H) 2.29-2.25 (m, 1 H) 1.90-1.84 (m, 2 H) 1.27-1.24 (m, 4 H); 13
C
NMR (100 MHz, CD3OD): δ 170.16, 160.34, 156.01, 138.52, 135.73, 130.97, 128.70,
122.81, 120.81, 119.54, 62.51, 62.07, 34.73, 29.43, 10.58, 9.46; HRMS calcd. for
C23H27N2O4 (M+H+) 395.1965, found 395.1946
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4-(4-(2-methyloxazol-4-yl)phenoxy)
phenyl)butyl dihydrogen phosphate (30a)
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30a was prepared using the same procedure as that described for compound 14a.
White solid (23mg, three steps 22.5% yield)
mp: 218-220 oC
;
1H NMR (300 MHz, CD3OD): δ 8.01 (s, 1 H) 7.61 (d, J = 8.4 Hz, 2
H) 7.21 (d, J = 8.4 Hz, 2 H) 6.91 (t, J = 6.9 Hz, 4 H) 3.95 (brs, 2 H) 3.66 (s, 2 H) 2.64
(q, J = 7.8 Hz, 2 H) 2.43 (s, 3 H) 1.94 (q, J = 5.7 Hz, 2 H); 13
C NMR (100 MHz,
CD3OD): δ 163.94, 159.00, 156.65, 141.23, 137.84, 134.94, 130.86, 127.99, 127.17,
120.39, 119.58, 65.79, 65.74, 62.48, 61.39, 61.32, 34.91, 29.33, 13.54; HRMS calcd.
for C21H26N2O7P (M+H+) 449.1472, found 449.1465
Synthesis of 2-amino-4-(4-(4-(2-ethyloxazol-4-yl)phenoxy)phenyl)-2-
(hydroxymethyl)butyl dihydrogen phosphate (30b)
30b was prepared using the same procedure as that described for compound 14a.
White solid (17mg, three steps 15.5% yield)
mp: 220-223 oC
;
1H NMR (300 MHz, CD3OD): δ 7.94-7.72 (m, 1 H) 7.39-7.18 (m, 4
H) 6.96-6.84 (m, 4 H) 3.96 (s, 2 H) 3.67 (s, 2 H) 2.69-2.64 (m, 2 H) 1.98-1.92 (m, 2 H)
1.41 (t, J = 7.8 Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ 169.75, 160.19, 156.05,
138.41, 137.97, 136.47, 130.93, 128.69, 123.33, 120.76, 119.54, 62.50, 62.03, 34.71,
29.41, 22.26, 10.65; HRMS calcd. for C22H28N2O7P (M+H+) 463.1629, found
463.1646
Synthesis of 2-amino-4-(4-(4-(2-cyclopropyloxazol-4-yl)phenoxy)phenyl)-2-
(hydroxymethyl)butyl dihydrogen phosphate (30c)
30c was prepared using the same procedure as that described for compound 14a.
White solid (18mg, three steps 14.7% yield)
mp: 140-143 oC
;
1H NMR(300 MHz, CD3OD): δ 7.92 (s, 1 H) 7.59 (d, J = 8.4 Hz, 2
H) 7.20 (d, J = 8.4 Hz, 2 H) 6.92 (d, J = 8.4 Hz, 2 H) 6.87 (d, J = 8.7 Hz, 2 H) 3.95 (s,
2 H) 3.68 (s, 2 H) 2.65-2.62 (m, 2 H) 2.09-2.05 (m, 1 H) 1.96-1.91 (m, 2 H) 1.03-1.01
(m, 4 H); 13
C NMR (100 MHz, CD3OD): δ 168.19, 158.96, 156.63, 141.20, 137.84,
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134.06, 130.87, 128.03, 127.25, 120.37, 119.54, 65.77, 62.49, 61.35, 61.28, 34.91,
30.74, 29.33, 9.57, 8.40; HRMS calcd. for C23H27N2O7P (M+H+) 475.1629, found
475.1586
Synthesis of diethyl 2-acetamido-2-(4-(4-(2-ethyl-1H-imidazol-4-yl)phenoxy)
phenethyl)malonate (31)
To a solution of 27b (1.0 g, 1.9 mmol) in xylene(20mL) was added acetamide (0.29
g, 3.8 mmol). The mixture was heated to reflux for 40h, then concentrated. The
residue was diluted with EtOAc(30mL), washed with brine, dried over Na2SO4,
filtered and concentrated. The residue was purified by silica gel flash column
chromatography (EtOAc/PE) to afford compound 31 (0.2g, 20.8% yield) as yellow
oil. 1H NMR (300 MHz, CDCl3): δ 7.63 (d, J = 8.4 Hz, 2 H) 7.13 (s, 1 H) 7.09 (d, J = 8.1
Hz, 2 H) 6.96 (d, J = 8.4 Hz, 2 H) 6.91 (d, J = 8.1 Hz, 2 H) 6.80 (brs, 1 H) 4.23-4.18
(m, 4 H) 2.81 (q, J = 7.8 Hz, 2 H) 2.69 (dd, J = 9.0 Hz, 6.6 Hz, 2 H) 2.46 (dd, J = 8.4
Hz, 7.8 Hz, 2 H) 2.01 (s, 3 H) 1.32 (t, J = 7.5 Hz, 3 H) 1.25 (t, J = 7.2 Hz, 6 H); ESI
(m/z) 508 (M+H+)
Synthesis of 2-amino-2-(4-(4-(2-ethyl-1H-imidazol-4-yl)phenoxy)phenethyl)
propane-1,3-diol (32)
32 was prepared using the same procedure as that described for compound 11a.
Yellow solid (0.1g, two steps 60.5% yield)
mp: 130-133 oC;
1H NMR (300 MHz, CD3OD): δ 7.63 (d, J = 8.4 Hz, 2 H) 7.62 (s, 1
H) 7.23 (d, J = 8.4 Hz, 2 H) 6.99 (d, J = 8.4 Hz, 2 H) 6.93 (d, J = 8.7 Hz, 2 H) 3.64 (s,
4 H) 2.99 (q, J = 7.8 Hz, 2 H) 2.66-2.60 (m, 2 H) 1.94-1.88 (m, 2 H) 1.37 (t, J = 7.5
Hz, 3 H); 13
C NMR (100 MHz, CD3OD): δ 160.39, 155.90, 150.90, 138.61, 134.17,
130.98, 128.36, 122.72, 120.88, 119.61, 114.77, 62.49, 62.05, 34.71, 29.42, 20.40,
11.89; HRMS calcd. for C23H28N3O3 (M+H+) 382.2125, found 382.2120
Synthesis of 2-amino-4-(4-(4-(2-ethyl-1H-imidazol-4-yl)phenoxy)phenyl)-2-
(hydroxymethyl)butyl dihydrogen phosphate (33)
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46
33 was prepared using the same procedure as that described for compound 14a.
White solid (3mg, three steps 5.1% yield)
mp: 125-128 oC ;
1H NMR (300 MHz, CD3OD): δ 8.47 (s, 1 H) 7.58 (d, J = 8.4 Hz, 2
H) 7.37 (d, J = 8.1 Hz, 2 H) 7.12 (d, J = 8.4 Hz, 2 H) 6.90 (d, J = 7.8 Hz, 2 H) 3.60 (s,
4 H) 3.14 (q, 2 H) 2.69-2.64 (m, 2 H) 1.98-1.92 (m, 2 H) 1.51 (t, J = 7.8 Hz, 3 H); 13
C
NMR (125 MHz, CD3OD): δ 170.75, 162.19, 153.05, 135.41, 138.97, 134.47, 132.93,
128.54, 123.77, 119.56, 119.23, 60.57, 60.03, 36.71, 31.50, 24.26, 13.66; HRMS
calcd. for C22H29N3O6P (M+H+) 462.1788, found 462.1775
Synthesis of 1-(4-bromophenyl)butan-1-one (35)
A mixture of butyric acid (25 mL, 277 mmol) and PCl3(10 mL, 111 mmol) was
stirred for 3h at 50-60°C, then cooled to room temperature and filtered. The filtrate
was added to a solution of bromobenzene(17g, 111mmol) in CH2Cl2(200mL). Then
AlCl3 (29 g, 222 mmol) was added in portions in 30min. The solution was then
allowed to return to room temperature and stirred for further 2 h. The mixture was
poured slowly into 2NHCl-ice mixture (100mL) and stirred for 1 h. The aqueous
phase was extracted with CH2Cl2 (20mL×3). The combined organic layers were
washed with saturated aq. NaHCO3 and brine, dried over Na2SO4, filtered and
concentrated, yielding crude product 35 (23.6g, 94% yield) as brown solid.
mp: 36-38 oC ;
1H NMR (300 MHz, CDCl3) δ: 7.82 (d, J = 8.7 Hz, 2H), 7.59 (d, J =
8.7 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H), 1.78 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). ESI (m/z)
227 (M+H) +
Synthesis of 1-(4-(2-fluorophenoxy)phenyl)butan-1-one (36a)
To a solution of 35 (8.4 g, 37.2 mmol) in DMF(80mL) was added 2-fluorophenol (5
g, 44.6 mmol), Cs2CO3 (14.5g, 44.6mmol) and CuBr (0.27g, 1.86mmol). The mixture
was heated for 20h at 150 °C under Ar2 protection, then cooled to room temperature,
filtered through celite to remove insoluble materials, and the filtrate was concentrated.
The residue was purified by silica gel flash column chromatography (EtOAc/PE) to
afford compound 36a (7.8g, 71.0% yield) as yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.95 (d, J = 8.7 Hz, 2H), 7.18 (m, 4H), 6.97 (d, J = 8.7
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Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 1.76 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). ESI (m/z)
259 (M+H) +
Synthesis of 1-(4-(3-fluorophenoxy)phenyl)butan-1-one (36b)
36b was prepared using the same procedure as that described for compound 36a.
Yellow oil (5.9g, 62.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J = 8.4 Hz, 2H), 7.30 (m, 1H), 7.03 (d, J = 8.4
Hz, 2H), 6.85 (m, 3H), 2.91 (t, J = 7.4 Hz, 2H), 1.77 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H).
ESI (m/z) 259 (M+H) +
Synthesis of 1-(4-(3-chlorophenoxy)phenyl)butan-1-one (36c)
36c was prepared using the same procedure as that described for compound 36a.
Yellow oil (1.2g, 50.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.97 (d, J = 8.7 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.16
(d, J = 7.8 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.95 (dd, J1 = 8.1 Hz, J2 =
2.4, 1H), 2.92 (t, J = 7.2 Hz, 2H), 1.77 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H). ESI (m/z)
275 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-butyrylphenoxy)-3-fluorophenyl)
-2-oxoethyl)malonate (37a)
37a was prepared using the same procedure as that described for compound 8a.
Yellow oil (1.9g, two steps 19.8% yield) 1H NMR (300 MHz, CDCl3) δ: 7.99 (d, J = 8.4 Hz, 2H), 7.79 (t, J = 10.5 Hz, 1H),
7.13 (m, 2H), 7.04 (d, J = 8.4 Hz, 2H), 4.27 (m, 6H), 2.92 (t, J = 7.2 Hz, 2H), 2.08 (s,
3H), 1.76 (m, 2H), 1.28 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). ESI (m/z) 516 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-butyrylphenoxy)-2-fluorophenyl)
-2-oxoethyl)malonate (37b)
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37b was prepared using the same procedure as that described for compound 8a.
Yellow solid (2.2g, two steps 28.1% yield)
mp: 18-21 oC;
1H NMR (300 MHz, CDCl3) δ: 8.03 (d, J = 8.7 Hz, 2H), 7.88 (t, J = 8.4
Hz, 1H), 7.13 (m, 2H), 6.85 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H), 6.75 (dd, J1 = 12.0 Hz,
J2 = 2.1 Hz, 1H), 4.24 (m, 6H), 2.94 (m, 2H), 2.03 (s, 3H), 1.78 (m, 2H), 1.25 (m, 6H),
1.02 (t, J = 7.4 Hz, 3H). ESI (m/z) 516 (M+H) +
Synthesis of diethyl 2-acetamido-2-(2-(4-(4-butyrylphenoxy)-2-chlorophenyl)
-2-oxoethyl)malonate (37c)
37c was prepared using the same procedure as that described for compound 8a.
Yellow solid (0.61g, two steps 29.1% yield)
mp: 44-46 oC;
1H NMR (300 MHz, CDCl3) δ: 8.02 (d, J = 8.4 Hz, 2H), 7.64 (d, J =
8.4 Hz, 1H), 7.10 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 4.28 (m, 6H), 2.94 (t, J = 7.2 Hz,
2H), 2.08 (s, 3H), 1.78 (m, 2H), 1.28 (m, 6H), 1.02 (t, J = 7.2 Hz, 3H). ESI (m/z) 532
(M+H) +
Synthesis of diethyl 2-acetamido-2-(4-(4-butylphenoxy)-3-fluorophenethyl)
malonate (38a)
38a was prepared using the same procedure as that described for compound 19a.
White solid (0.62g, 37.0% yield)
mp: 63-66 oC;
1H NMR (300 MHz, CDCl3) δ: 7.10 (d, J = 8.7 Hz, 2H ), 6.94 (m, 2H),
6.83 (m, 3H), 4.24 (m, 4H), 2.68 (m, 2H), 2.57 (m, 2H), 2.45 (m, 2H), 2.03 (s, 3H),
1.57 (m, 2H), 1.34 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). ESI (m/z)
488 (M+H)+
Synthesis of diethyl 2-acetamido-2-(4-(4-butylphenoxy)-2-fluorophenethyl)
malonate (38b)
38b was prepared using the same procedure as that described for compound 19a.
Yellow oil (0.62g, 32.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, J = 7.5 Hz, 2H), 7.07 (t, J = 8.7 Hz, 1H), 6.91
(d, J = 6.6 Hz, 2H), 6.66 (m, 2H), 4.22 (m, 4H), 2.61 (m, 4H), 2.45 (m, 2H), 2.05 (s,
3H), 1.60 (m, 2H), 1.38 (m, 2H), 1.26 (m, 6H), 0.93 (t, J = 7.1 Hz, 3H). ESI (m/z) 488
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(M+H) +
Synthesis of diethyl 2-acetamido-2-(4-(4-butylphenoxy)-2-chlorophenethyl)
malonate (38c)
38c was prepared using the same procedure as that described for compound 19a.
Crude product as yellow oil (1.0g, 70.0% yield)
ESI (m/z) 504 (M+H) +
Synthesis of 2-amino-2-(4-(4-butylphenoxy)-3-fluorophenethyl)propane-1,3-diol
(39a)
39a was prepared using the same procedure as that described for compound 11a.
White solid (386mg, two steps 71.5% yield)
m.p.: 176-179 °C. 1H NMR (300 MHz, CD3OD) δ: 7.05 (m, 3H), 6.94 (m, 1H), 6.88
(m, 1H), 6.73 (d, J = 8.4 Hz, 2H), 3.61 (s, 4H), 2.60 (m, 2H), 2.49 (t, J = 7.7 Hz, 2H),
1.88 (m, 2H), 1.47 (m, 2H), 1.26 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13
C NMR (400
MHz, CD3OD) δ: 157.0, 155.5 (J = 246 Hz), 143.5 (J = 12 Hz), 139.9 (J = 6 Hz),
138.9, 130.6, 125.6 (J = 3 Hz), 122.9, 117.9, 117.7 (J = 19 Hz), 62.5, 62.0, 35.8, 35.1,
34.4, 29.4, 23.3, 14.3. HRMS calcd for C21H29FNO3 (M+H)+
362.2126; found:
362.2128.
Synthesis of 2-amino-2-(4-(4-butylphenoxy)-2-fluorophenethyl)propane-1,3-diol
(39b)
39b was prepared using the same procedure as that described for compound 11a.
White solid (350mg, two steps 52.9% yield)
m.p.: 165-167 °C. 1H NMR (300 MHz, CD3OD) δ: 7.13 (t, J = 8.7 Hz, 1H), 7.07 (d, J
= 8.1 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 6.58 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H), 6.52
(dd, J1 = 11.4 Hz, J2 = 2.4 Hz, 1H), 3.59 (s, 4H), 2.57 (m, 2H), 2.48 (t, J = 7.7 Hz, 2H),
1.83 (m, 2H), 1.48 (m, 2H), 1.23 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13
C NMR (400
MHz, CD3OD) δ: 162.6 (J = 243 Hz), 159.2 (J = 11 Hz), 155.6, 140.0, 132.2 (J = 7
Hz), 130.9, 123.2 (J = 16 Hz), 120.4, 114.8, 106.4 (J = 26 Hz), 62.5, 62.0, 35.9, 35.0,
33.2, 23.3, 22.9, 14.3. HRMS calcd for C21H29FNO3 (M+H)+362.2126; found:
362.2135.
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Synthesis of 2-amino-2-(4-(4-butylphenoxy)-2-chlorophenethyl)propane-1,3-diol
(39c)
39c was prepared using the same procedure as that described for compound 11a.
White solid (61mg, two steps 78.0% yield)
m.p.: 208-210 °C. 1H NMR (300 MHz, CD3OD) δ: 7.25 (d, J = 8.7 Hz, 1H), 7.15 (d, J
= 8.4 Hz, 2H), 6.87 (m, 2H), 6.84 (s, 1H), 6.79 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 3.68
(s, 4H), 2.72 (m, 2H), 2.56 (t, J = 7.7 Hz, 2H), 1.88 (m, 2H), 1.55 (m, 2H), 1.32 (m,
2H), 0.89 (t, J = 7.4 Hz, 3H). 13
C NMR (400 MHz, CD3OD) δ: 158.7, 155.6, 140.1,
135.2, 134.1, 132.4, 130.9, 120.4, 119.9, 118.0, 62.5, 62.0, 35.9, 35.0, 33.1, 27.4, 23.3,
14.3. HRMS calcd for C21H29ClNO3 (M+H)+
378.1830; found: 378.1838.
Synthesis of 2-amino-4-(4-(4-butylphenoxy)-3-fluorophenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (40a)
40a was prepared using the same procedure as that described for compound 14a.
White solid (36mg, three steps 33.7% yield)
m.p.: 185-187 °C. 1H NMR (300 MHz, CD3OD) δ: 7.08 (m, 3H), 6.98 (m, 1H), 6.91
(m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 3.94 (m, 2H), 3.65 (m, 2H), 2.65 (m, 2H), 2.52 (t, J
= 7.7 Hz, 2H), 1.94 (m, 2H), 1.52 (m, 2H), 1.29 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). 13
C
NMR (600 MHz, CD3OD) δ: 157.0, 155.5 (J = 245 Hz), 143.6 (J = 12 Hz), 139.8 (J =
6 Hz), 138.9, 130.6, 125.7 (J = 3 Hz), 122.9, 118.0, 117.8 (J = 19 Hz), 65.7, 62.5, 61.3,
35.8, 35.1, 34.6, 29.3, 23.3, 14.3. HRMS calcd for C21H30FNO6P (M+H)+ 442.1789;
found: 442.1810.
Synthesis of 2-amino-4-(4-(4-butylphenoxy)-2-fluorophenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (40b)
40b was prepared using the same procedure as that described for compound 14a.
White solid (32mg, three steps 25.5% yield)
m.p.: 195-197 °C. 1H NMR (300 MHz, CD3OD) δ: 7.20 (t, J = 8.6 Hz, 1H), 7.13 (d, J
= 8.4 Hz, 2H), 6.85(d, J = 8.7 Hz, 2H), 6.64 (dd, J1 = 8.1 Hz, J2= 1.8 Hz, 1H), 6.58
(dd, J1 = 11.4 Hz, J2 = 2.4 Hz, 1H), 3.96 (m, 2H), 3.66 (m, 2H), 2.64 (m, 2H), 2.55 (t,
J = 7.7 Hz, 2H), 1.91 (m, 2H), 1.54 (m, 2H), 1.28 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H).
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13C NMR (600 MHz, CD3OD) δ: 162.6 (J = 243 Hz), 159.3 (J = 10 Hz), 155.7, 140.0,
132.3 (J = 6 Hz), 130.9, 123.1 (J = 16 Hz), 120.4, 114.9, 106.4 (J = 26 Hz), 65.8, 62.5,
61.2, 35.9, 35.0, 33.4, 23.3, 22.9, 14.3. HRMS calcd for C21H30FNO6P (M+H)+
442.1789; found: 442.1808.
Synthesis of 2-amino-4-(4-(4-butylphenoxy)-2-chlorophenyl)-2-(hydroxymethyl)
butyl dihydrogen phosphate (40c)
40c was prepared using the same procedure as that described for compound 14a.
White solid (5mg, three steps 8.6% yield)
m.p.: 205-207 °C. 1H NMR (400 MHz, CD3OD) δ: 7.27 (d, J = 8.0 Hz, 1H), 7.16 (d, J
= 8.0 Hz, 2H), 6.88 (m, 3H), 6.81 (d, J = 8.0 Hz, 1H), 3.99 (m, 2H), 3.71 (m, 2H),
2.76 (m, 2H), 2.58 (m, 2H), 1.92 (m, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.92 (t, J = 8.0
Hz, 3H). 13
C NMR (500 MHz, DMSO) δ: 156.4, 153.9, 138.2, 133.4, 131.5, 129.9,
119.1, 118.7, 117.3, 64.6, 63.4, 61.0, 34.1, 33.3, 31.7, 25.7, 21.8, 13.9. HRMS calcd
for C21H30ClNO6P (M+H)+ 458.1494; found: 458.1498.
Synthesis of 1-(4-bromophenyl)-2-chloroethanone (41)
41 was prepared using the same procedure as that described for compound 7a.
Yellow solid (1.4g, 95.0% yield)
mp: 116-118 oC ;
1H NMR (300 MHz, CDCl3) δ: 7.83 (d, J = 8.7 Hz, 2H), 7.65 (d, J =
8.7 Hz, 2H), 4.65 (s, 2H). ESI (m/z) 232 (M+H) +
Synthesis of 4-(4-bromophenyl)-2-ethyloxazole (42)
42 was prepared using the same procedure as that described for compound 28a.
Yellow solid (0.54g, two steps 35.7% yield)
mp: 98-100 oC;
1H NMR (300 MHz, CDCl3) δ: 7.81 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H),
7.51 (d, J = 8.4 Hz, 2H), 2.84 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H). ESI (m/z)
252 (M+H) +
Synthesis of 4-(4-(3-chlorophenoxy)phenyl)-2-ethyloxazole (43)
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43 was prepared using the same procedure as that described for compound
36a.Yellow oil (3.1g, 66.0% yield) 1H NMR (300 MHz, CDCl3) δ: 7.78 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.25 (m, 1H),
7.03 (m, 3H), 6.89 (d, J = 8.1 Hz, 1H), 2.85 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz,
3H). ESI (m/z) 300 (M+H) +
Synthesis of Diethyl 2-acetamido-2-(2-(2-chloro-4-(4-(2-ethyloxazol-4-yl)phenoxy)
phenyl)-2-oxoethyl)malonate (44)
44 was prepared using the same procedure as that described for compound 8a.
Yellow solid (2.2g, two steps 38.3% yield)
mp: 78-80 oC;
1H NMR (300 MHz, CDCl3) δ: 7.82 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H),
7.63 (d, J = 9.0 Hz, 1H), 7.10 (m, 3H), 7.00 (d, J = 2.4 Hz, 1H), 6.91 (dd, J1 = 8.7 Hz,
J2 = 2.4 Hz, 1H), 4.27 (m, 6H), 2.88 (q, J = 7.6 Hz, 2H), 2.01 (s, 3H), 1.40 (t, J = 7.5
Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H). ESI (m/z) 557 (M+H) +
Synthesis of Diethyl 2-acetamido-2-(2-chloro-4-(4-(2-ethyloxazol-4-yl)phenoxy)
phenethyl)malonate (45)
45 was prepared using the same procedure as that described for compound 9a.
Yellow solid (0.91g, 72.0% yield)
mp: 68-69 oC;
1H NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H),
7.14 (d, J = 8.4 Hz, 1H), 7.01 (m, 3H), 6.85 (m, 2H), 4.25 (m, 4H), 2.85 (q, J = 7.6 Hz,
2H), 2.65 (m, 2H), 2.55 (m, 2H), 2.07 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H), 1.28 (m, 6H).
ESI (m/z) 543(M+H) +
Synthesis of 2-amino-2-(2-chloro-4-(4-(2-ethyloxazol-4-yl)phenoxy)phenethyl)
propane-1,3-diol (46)
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46 was prepared using the same procedure as that described for compound 11a.
White solid (88mg, two steps 62.0% yield)
m.p.: 198-200 °C. 1H NMR (300 MHz, CD3OD) δ: 8.10 (s, 1H), 7.64 (d, J = 8.4 Hz,
2H), 7.25 (d, J = 8.4 Hz, 1H), 6.95 (m, 3H), 6.84 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H),
3.65 (s, 4H), 2.81 (q, J = 7.7 Hz, 2H), 2.72 (m, 2H), 1.86 (m, 2H), 1.29 (t, J = 7.7 Hz,
3H). 13
C NMR (400 MHz, CD3OD) δ: 168.6, 158.2, 157.7, 140.1, 135.5, 135.4, 135.0,
132.5, 128.4, 127.2, 120.8, 120.3, 118.8, 62.5, 61.9, 33.0, 27.4, 22.4, 11.3. HRMS
calcd for C22H26ClN2O4 (M+H) +
417.1581; found: 417.1582.
Synthesis of 2-amino-4-(2-chloro-4-(4-(2-ethyloxazol-4-yl)phenoxy)phenyl)-2-
(hydroxymethyl)butyl dihydrogen phosphate (47)
47 was prepared using the same procedure as that described for compound 14a.
White solid (1.6mg, three steps 12.0% yield)
m.p.: 125-128 °C. 1H NMR (500 MHz, CD3OD) δ: 8.05 (s, 1H), 7.68 (d, J = 8.0 Hz,
2H), 7.30 (d, J = 8.0 Hz, 1H), 6.98 (m, 3H), 6.88 (m, 1H), 3.96 (m, 2H), 3.68 (m, 2H),
2.77 (m, 4H), 1.90 (m, 2H), 1.31 (t, J = 8.0 Hz, 3H). 13
C NMR (500 MHz, CD3OD) δ:
168.5, 158.3, 158.1, 141.3, 135.7, 135.4, 135.3, 132.9, 128.5, 120.9, 120.6, 119.0,
66.4, 63.4, 61.0, 33.9, 27.7, 22.7, 11.9. HRMS calcd for C22H27ClN2O7P (M+H)+
497.1244; found: 497.1242.
Synthesis of diethyl 2-(2-([1,1'-biphenyl]-4-yl)-2-oxoethyl)-2-acetamidomalonate
(49)
49 was prepared using the same procedure as that described for compound 17.
Crude product as yellow oil (6.0g, two steps 62.0% yield)
ESI (m/z) 412 (M+H) +
434 (M+Na+)
Synthesis of diethyl 2-(2-([1,1'-biphenyl]-4-yl)ethyl)-2-acetamidomalonate (50)
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50 was prepared using the same procedure as that described for compound 9a.
Yellow oil (5.0g, 86.9% yield) 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J = 7.8 Hz, 2 H) 7.50 (d, J = 7.8 Hz, 2 H) 7.42
(t, J = 7.5 Hz, 2 H) 7.33 (d, J = 7.2 Hz, 1 H) 7.22 (d, J = 8.4 Hz, 2 H) 6.78 (brs, 1 H)
4.26-4.16 (m, 4 H) 2.73 (dd, J = 10.5 Hz, 7.2 Hz, 2 H) 2.53 (dd, J = 9.3 Hz, 5.7 Hz, 2
H) 1.98 (s, 3 H) 1.25 (t, J = 7.2 Hz, 6 H); ESI (m/z) 398 (M+H+) 420 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4'-(2-chloroacetyl)-[1,1'-biphenyl]-4-yl)
ethyl)malonate (51)
51 was prepared using the same procedure as that described for compound 26.
Yellow solid (5.2g, 87.3% yield)
mp: 80-83 oC;
1H NMR (300 MHz, CDCl3): δ 8.02 (d, J = 8.4 Hz, 2 H) 7.69 (d, J =
8.1 Hz, 2 H) 7.54 (d, J = 8.1 Hz, 2 H) 7.27 (d, J = 8.4 Hz, 2 H) 6.79 (brs, 1 H) 4.73 (s,
2 H) 4.27-4.19 (m, 4 H) 2.73 (dd, J = 10.8 Hz, 6.3 Hz, 2 H) 2.53 (dd, J = 9.3 Hz, 5.4
Hz, 2 H) 2.04 (s, 3 H) 1.26 (t, J = 7.2 Hz, 6 H); ESI (m/z) 474 (M+H+) 496 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4'-(2-methyloxazol-4-yl)-[1,1'-biphenyl]
-4-yl)ethyl)malonate (52a)
52a was prepared using the same procedure as that described for compound 28a.
Yellow solid (0.9g, two steps 62.8% yield)
mp: 123-125 oC;
1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1 H) 7.77 (d, J = 8.4 Hz, 2 H)
7.60 (d, J = 8.7 Hz, 2 H) 7.53 (d, J = 8.1 Hz, 2 H) 7.23 (d, J = 8.4 Hz, 2 H) 6.78 (brs,
1 H) 4.27-4.18 (m, 4 H) 2.73 (dd, J = 10.5 Hz, 6.6 Hz, 2 H) 2.55-2.50 (m, 5 H) 1.99 (s,
3 H) 1.25 (t, J = 7.2 Hz, 6 H); ESI(m/z) 479 (M+H+) 501 (M+Na
+)
Synthesis of diethyl 2-acetamido-2-(2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]
-4-yl)ethyl)malonate (52b)
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52b was prepared using the same procedure as that described for compound 28a.
Yellow solid (0.95g, two steps 72.2% yield)
mp: 131-134 oC;
1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1 H) 7.77 (d, J = 8.4 Hz, 2 H)
7.59 (d, J = 8.1 Hz, 2 H) 7.52 (d, J = 8.1 Hz, 2 H) 7.22 (d, J = 8.4 Hz, 2 H) 6.78 (brs,
1 H) 4.27-4.16 (m, 4 H) 2.82 (t, J = 7.2 Hz, 2 H) 2.73 (dd, J = 10.5 Hz, 6.6 Hz, 2 H)
2.52 (dd, J = 15.9 Hz, 9.3 Hz, 2 H) 1.99 (s, 3 H) 1.89-1.79 (m, 2 H) 1.25 (t, J = 7.2 Hz,
6 H) 1.03 (t, J = 7.2 Hz, 3 H); ESI (m/z) 507 (M+H+) 529 (M+Na
+)
Synthesis of 2-amino-2-(2-(4'-(2-methyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl)
propane-1,3-diol (53a)
53a was prepared using the same procedure as that described for compound 11a.
White solid (0.15g, two steps 64.5% yield)
mp: 78-80 oC;
1H NMR (300 MHz, CD3OD): δ 8.21 (s, 1 H) 7.72 (d, J = 7.8 Hz, 2 H)
7.62 (d, J = 8.7 Hz, 2 H) 7.54 (d, J = 8.4 Hz, 2 H) 7.28 (d, J = 8.4 Hz, 2 H) 3.66 (s, 4
H) 2.69-2.64 (m, 2 H) 2.52 (s, 3 H) 1.97-1.91 (m, 2 H); 13
C NMR (100 MHz,
CD3OD): δ 164.62, 142.11, 141.93, 140.61, 139.70, 135.97, 130.15, 129.91, 128.66,
128.42, 126.99, 62.53, 62.07, 34.58, 29.76, 13.53; HRMS calcd. for C21H25N2O3
(M+H+) 353.1865, found 353.1872
Synthesis of 2-amino-2-(2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl)
propane-1,3-diol (53b)
53b was prepared using the same procedure as that described for compound 11a.
White solid (0.42g, two steps 71.6% yield)
mp: 170-172 oC;
1H NMR (300 MHz, DMSO): δ 8.52 (s, 1 H) 7.83 (d, J = 8.4 Hz, 2
H) 7.70 (d, J = 8.7 Hz, 2 H) 7.61 (d, J = 8.1 Hz, 2 H) 7.29 (d, J = 7.8 Hz, 2 H) 4.49
(brs, 2 H) 3.34 (brs, 1 H) 3.31-3.22 (m, 4 H) 2.78 (t, J = 7.2 Hz, 2 H) 2.66-2.61 (m, 2
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H) 1.82-1.70 (m, 2 H) 1.56-1.51 (m, 2 H) 0.96 (t, J = 7.5 Hz, 3 H); 13
C NMR (100
MHz, DMSO): δ 164.60, 142.90, 139.29, 139.17, 136.72, 134.60, 129.83, 128.79,
126.64, 126.30, 125.53, 65.38, 55.42, 36.73, 29.24, 28.60, 19.95, 13.46; HRMS calcd.
for C23H29N2O3 (M+H+) 381.2178, found 381.2183
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4'-(2-methyloxazol-4-yl)-[1,1'-
biphenyl]-4-yl)butyl dihydrogen phosphate (54a)
54a was prepared using the same procedure as that described for compound 14a.
White solid (30mg, three steps 34.0% yield)
mp: 220-223 oC
;
1H NMR (300 MHz, CD3OD): δ 8.12 (s, 1 H) 7.73 (d, J = 8.4 Hz, 2
H) 7.60 (d, J = 8.4 Hz, 2 H) 7.54 (d, J = 7.8 Hz, 2 H) 7.28 (d, J = 8.1 Hz, 2 H) 3.66 (s,
4 H) 2.70-2.64 (m, 2 H) 2.46 (s, 3 H) 1.97-1.91 (m, 2 H); 13
C NMR (125 MHz,
CD3OD): δ 164.08, 141.85, 141.78, 141.43, 139.84, 135.57, 131.09, 129.88, 128.13,
127.99, 126.90, 62.59, 62.00, 58.33, 52.66, 52.61, 34.62, 29.76, 13.56; HRMS calcd.
for C23H29N2O3 (M+H+) 433.1478, found 433.1485
Synthesis of 2-amino-2-(hydroxymethyl)-4-(4'-(2-propyloxazol-4-yl)-[1,1'-
biphenyl]-4-yl)butyl dihydrogen phosphate (54b)
54b was prepared using the same procedure as that described for compound 14a.
White solid (50mg, three steps 45.2% yield)
mp: 110-113 oC
;
1H NMR (300 MHz, CD3OD): δ 8.09 (s, 1 H) 7.68-7.16 (m, 8 H)
4.97-4.92 (m, 6 H) 3.97-3.56 (m, 4 H) 2.73-2.55 (m, 4 H) 1.95-1.74 (m, 4 H) 0.78 (t, J
= 7.8 Hz, 3 H); 13
C NMR (100 MHz, CD3OD) δ 164.60, 143.26, 141.78, 138.45,
135.37, 130.98, 130.08, 129.47, 128.95, 127.97, 126.90, 67.14, 66.57, 63.04, 36.77,
30.79, 30.05, 21.62, 13.92; HRMS calcd. for C23H30N2O6P (M+H+) 461.1836, found
461.1826
References
1 (a)A. Shenker, P. Goldsmith, C. G. Unson and A. M. Spiegel, J. Biol. Chem., 1991, 266, 9309-9313;
(b)C. Ballatore, J. H. Soper, F. Piscitelli, M. James, L. Huang, O. Atasoylu, D. M. Huryn, J. Q.
Trojanowski, V. M. Lee, K. R. Brunden and A. B. Smith, J. Med. Chem., 2011, 54, 6969-6983.
Electronic Supplementary Material (ESI) for Medicinal Chemistry CommunicationsThis journal is © The Royal Society of Chemistry 2013
57
2 M. Forrest, S.-Y. Sun, R. Hajdu, J. Bergstrom, D. Card, G. Doherty, J. Hale, C. Keohane, C. Meyers,
J. Milligan, S. Mills, N. Nomura, H. Rosen, M. Rosenbach, G.-J. Shei, I. I. Singer, M. Tian, S. West,
V. White, J. Xie, R. L. Proia, and S. Mandala, J. Pharmacol. Exp. Ther., 2004, 309, 758-768.
3 A. L. Parrill, S. Lima and S. Spiegel, Sci Signal, 2012, 5, pe23.
4 M. A. Hanson, C. B. Roth, E. Jo, M. T. Griffith, F. L. Scott, G. Reinhart, H. Desale, B. Clemons, S.
M. Cahalan, S. C. Schuerer, M. G. Sanna, G. W. Han, P. Kuhn, H. Rosen and R. C. Stevens, Science,
2012, 335, 851-855.
5 A. N. Jain, J. Med. Chem., 2003, 46, 499-511.
6 J. Sun, S. Cai, N. Yan and H. Mei, Eur. J. Med. Chem., 2010, 45, 1008-1014.
7 B. L. Bush and R. B. Nachbar, Jr., J. Comput. Aided Mol. Des., 1993, 7, 587-619.
Electronic Supplementary Material (ESI) for Medicinal Chemistry CommunicationsThis journal is © The Royal Society of Chemistry 2013